Evidence Repository
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_001482.3(GATM):c.1257G>A (p.Gln419=)

CA7542750

509542 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 8950f619-eba0-4875-b119-ebf20a38aa31
Approved on: 2022-06-06
Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.1257G>A
NM_001482.3(GATM):c.1257G>A (p.Gln419=)
NC_000015.10:g.45362124C>T
CM000677.2:g.45362124C>T
NC_000015.9:g.45654322C>T
CM000677.1:g.45654322C>T
NC_000015.8:g.43441614C>T
NG_011674.1:g.21659G>A
NG_011674.2:g.45194G>A
ENST00000396659.8:c.1257G>A
ENST00000674905.1:c.*219G>A
ENST00000675158.1:c.*157G>A
ENST00000675323.1:c.*1759G>A
ENST00000675701.1:c.1197G>A
ENST00000675974.1:n.3806G>A
ENST00000676090.1:c.*1988G>A
ENST00000396659.7:c.1257G>A
ENST00000558362.5:n.2913G>A
NM_001482.2:c.1257G>A
NM_001321015.1:c.870G>A
NM_001321015.2:c.870G>A
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Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 3
PM2_Supporting BP7 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_001482.3:c.1257G>A (p.Gln419=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not highly conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30612 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 509542). Although this variant is rare (meeting PM2_Supporting), it has been classified as likely benign by the ClinGen CCDS VCEP based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GATM-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30612 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting).
BP7
No significant impact to splice consensus sequence, nucleotide is not highly conserved (Moderately conserved nucleotide).
BP4
No predicted impact on splicing by SpliceAI and varSEAK.
Curation History
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