14-100335036-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_ModerateBS2_Supporting
The NM_004184.4(WARS1):c.1255G>A(p.Asp419Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,060 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_004184.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WARS1 | NM_004184.4 | c.1255G>A | p.Asp419Asn | missense_variant, splice_region_variant | Exon 11 of 11 | ENST00000392882.7 | NP_004175.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000435 AC: 108AN: 248198Hom.: 0 AF XY: 0.000625 AC XY: 84AN XY: 134394
GnomAD4 exome AF: 0.000257 AC: 376AN: 1460798Hom.: 4 Cov.: 30 AF XY: 0.000381 AC XY: 277AN XY: 726568
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74452
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities Pathogenic:2
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 35815345). In silico tool predictions suggest no damaging effect of the variant on gene or gene product [REVEL: 0.30 (<0.4); 3Cnet: 0.07 (<0.15, specificity 0.78 and negative predicitive value 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with WARS1 related disorder (ClinVar ID: VCV002499496 /PMID: 35815345). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at