Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000518.5(HBB):c.92+5G>C

CA125310

15447 (ClinVar)

Gene: HBB (HGNC:3043)

Condition: beta-thalassemia HBB/LCRB (MONDO:0013517)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2466639d-2e77-42b7-9452-ce584ef83a72

Approved on: 2026-04-30

Published on: 2026-04-30

HGVS expressions

NM_000518.5:c.92+5G>C

NM_000518.5(HBB):c.92+5G>C

NC_000011.10:g.5226925C>G

CM000673.2:g.5226925C>G

NC_000011.9:g.5248155C>G

CM000673.1:g.5248155C>G

NC_000011.8:g.5204731C>G

NG_000007.3:g.70691G>C

NG_059281.1:g.5147G>C

ENST00000647020.1:c.92+5G>C

ENST00000335295.4:c.92+5G>C

ENST00000380315.2:c.92+5G>C

ENST00000485743.1:n.143+5G>C

ENST00000633227.1:c.76+21G>C

NM_000518.4:c.92+5G>C

Pathogenic

PS4 PP3 PM3 PS3_Supporting PP1_Strong

PM2 PM1 PM5 BA1 PVS1 BS1 BP7

Evidence Links 0

Expert Panel

Hemoglobinopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hemoglobinopathy VCEP

The c.92+5G>C variant in HBB is an intronic variant lying in the 5’ splice site consensus sequence. This variant has been reported in 4 unrelated individuals displaying a hematological phenotype consistent with β-thalassemia trait (low MCV (<79 fL), low MCH (<27 pg) and increased HbA2 (>3.5%)), giving a total score of 6 (PS4; PMID: 27690257; 23425159; 26291970; 29651865). This variant was found to co-segregate with beta-thalassemia (e.g., anemia, transfusion requirements and/or hepatosplenomegaly) in 4 affected individuals from different families. There were two unaffected segregations from the same family, giving a LOD score of 2.66 (PP1_S; PMID: 27690257; 2342515926291970; 29651865). This variant has been detected in two homozygous individuals with transfusion-dependent thalassemia, giving a score of 1 (PM3; PMID: 27690257; 23425159). The computational predictor SpliceAI predicts that this variant may affect splicing by disrupting the donor splice site of intron I of HBB (Δ score 0.81; VCEP threshold >0.3) (PP3). Transfection of cell cultures with constructs bearing the cloned mutant gene showed that this variant significantly reduces HBB gene expression (low RNA levels) and impacts splicing by producing both the normal and three abnormally spliced RNA products (PS3_P; PMID: 6188062). The highest population minor allele frequency in gnomAD v4.1 is 0.004481 (442/91042 alleles) in South Asian, exceeding the ClinGen Hemoglobinopathy VCEP BS1 threshold (≥0.001). However, this variant is on the VCEP exclusion list for BA1/BS1; therefore, these criteria were not applied. In summary, this variant meets criteria to be classified as pathogenic for beta-thalassemia HBB/LCRB (MONDO:0013517) in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VCEP (specification version 1.0.0): PS4, PP1_S, PM3,PP3, PS3_P.

PS4

This variant has been reported in 4 unrelated probands meeting low MCV (<79 fL), low MCH (<27 pg) and increased HbA2 (>3.5%). Total score is 6 [PMID: 27690257; PMID: 23425159; PMID: 26291970; PMID: 29651865].

PP3

The computational predictor SpliceAI gives a Δ score of 0.81 for donor loss, which is above threshold >0.3, predicting that the variant may affect splicing by disrupting the donor splice site of intron I of HBB.

PM3

This variant has been detected in 2 individuals with transfusion-dependent thalassaemia. Both were homozygous for the variant. Total PM3 points: 1 [PMID: 27690257; PMID: 23425159].

PS3_Supporting

Transfection of cell cultures with constructs bearing the cloned mutant gene showed that this variant significantly reduces HBB gene expression (low RNA levels) and impacts splicing by producing both the normal and three abnormally spliced RNA products [PMID: 6188062].

PP1_Strong

The variant has been reported to segregate with disease in 4 affected family members from 4 families. The total number of unaffected segregations is 2. The LOD score is 2.66

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Found in the 5' splice site consensus sequence. This variant does not reside within a region of HBB that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Hemoglobinopathy VCEP.

PM5

Two different variants [c.92+5G>T; c.92+5G>A] [VCV000015448.17; VCV000015449.15] in the same base site have been classified as pathogenic for β-thalassemia with a 2-star review status by ClinVar. Splicing predictor SpliceAI predicts a splicing impact for both variants c.92+5G>T: Splice AI Δ score 0.73 for donor loss c.92+5G>A: Splice AI Δ score 0.76 for donor loss

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PVS1

This is an intron variant [SO:0001627], not a null variant as defined by the criterion.

BS1

The highest population minor allele frequency in gnomAD v4.1 is 0.004481 (442/91042 alleles) in South Asian, exceeding the ClinGen Hemoglobinopathy VCEP BS1 threshold (≥0.001). However, this variant is on the VCEP exclusion list for BA1/BS1; therefore, these criteria were not applied.

BP7

This is an intron variant [SO:0001627], not a synonymous (silent) variant as defined by the criterion.

Curation History

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