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]

Link to SEPIO compliant JSON-LD document

Variant: NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser)

CA7331374

479636 (ClinVar)

Gene: DICER1

Condition: dicer1 syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e91d9267-aede-4514-ba57-8eb86a59b69b

Approved on: 2022-10-25

Published on: 2022-11-03

HGVS expressions

NM_177438.3:c.1904A>G

NM_177438.3(DICER1):c.1904A>G (p.Asn635Ser)

NC_000014.9:g.95115670T>C

CM000676.2:g.95115670T>C

NC_000014.8:g.95582007T>C

CM000676.1:g.95582007T>C

NC_000014.7:g.94651760T>C

NG_016311.1:g.46753A>G

ENST00000343455.8:c.1904A>G

ENST00000393063.6:c.1904A>G

ENST00000526495.6:c.1904A>G

ENST00000532939.3:c.1904A>G

ENST00000556045.6:c.1904A>G

ENST00000675995.1:c.*220A>G

ENST00000343455.7:c.1904A>G

ENST00000393063.5:c.1904A>G

ENST00000526495.5:c.1904A>G

ENST00000527414.5:c.1904A>G

ENST00000532458.1:n.493A>G

ENST00000541352.5:c.1904A>G

NM_001195573.1:c.1904A>G

NM_001271282.2:c.1904A>G

NM_001291628.1:c.1904A>G

NM_030621.4:c.1904A>G

NM_177438.2:c.1904A>G

NM_001271282.3:c.1904A>G

NM_001291628.2:c.1904A>G

NM_001395677.1:c.1904A>G

NM_001395678.1:c.1904A>G

NM_001395679.1:c.1904A>G

NM_001395680.1:c.1904A>G

NM_001395682.1:c.1904A>G

NM_001395683.1:c.1904A>G

NM_001395684.1:c.1904A>G

NM_001395685.1:c.1904A>G

NM_001395686.1:c.1622A>G

NM_001395687.1:c.1499A>G

NM_001395688.1:c.1499A>G

NM_001395689.1:c.1499A>G

NM_001395690.1:c.1499A>G

NM_001395691.1:c.1337A>G

NM_001395692.1:c.1904A>G

NM_001395693.1:c.1904A>G

NM_001395694.1:c.1904A>G

NM_001395695.1:c.1904A>G

NM_001395696.1:c.1499A>G

NM_001395697.1:c.221A>G

NM_001395698.1:c.1499A>G

NR_172715.1:n.2322A>G

NR_172716.1:n.2249A>G

NR_172717.1:n.2416A>G

NR_172718.1:n.2416A>G

NR_172719.1:n.2249A>G

NR_172720.1:n.2249A>G

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

BA1 BP2 BP4 BP7 BS2 BS4 BS3 BS1 PP4 PP1 PP3 PM2 PM1 PM5 PS2 PS4 PS3 PS1

Evidence Links 0

Expert Panel

DICER1 and miRNA-Processing Gene VCEP

Criteria Specification Information

Criteria Specification: ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

DICER1 and miRNA-Processing Gene VCEP

The NM_177438.2:c.1904A>G variant in DICER1 is a missense variant predicted to cause substitution of Aspartic Acid by Serine at amino acid 635 (p.Asp635Ser). This variant received 0 phenotype points across 16 probands, including 3 unrelated females without tumors through age 50 (GTRs: 61756, 500031, PMID: 33718253) (PS4 and BS2 are not met). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5; however, the splice site predictors MaxEntScan and SpliceAI indicate creation of a new donor splice site (BP4 and PP3 not met). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: No criteria. (Bayesian Points: 0; VCEP specifications version 1.1.0; 10/25/2022).

BA1

The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).

BP2

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

BP4

The computational predictor REVEL gives a score of 0.398, which is below the threshold of 0.5, but the splice site predictors MaxEntScan and SpliceAI indicate a new donor splice site is created that may compete with the native donor splice site (BP4 and PP3 not met). REVEL = 0.398 < 0.5 SpliceAI Donor Gain = 0.84 (no loss of native donor) MaxEntScan native donor = 7.37, 7.37; new donor = 0, 4.29

BP7

Missense variant

BS2

This variant has been seen in 3 unrelated females without tumors through age 50 in at least one testing laboratory

BS4

No segregation info

BS3

No experimental data found

BS1

The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).

PP4

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

PP1

No segregation info

PP3

PM2

The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00003 (1/30526 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met).

PM1

This variant does not reside within a region of the RNAse IIIb domain that is defined as a mutational hotspot or critical functional domain by the ClinGen DICER1 VCEP (PM1 not met).

PM5

None observed

PS2

No info

PS4

This variant received 0 phenotype points across 16 probands.

PS3

No experimental data found

PS1

None observed

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