rs773601814
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_015665.6(AAAS):c.938T>C(p.Val313Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V313V) has been classified as Likely benign.
Frequency
Consequence
NM_015665.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AAAS | NM_015665.6 | c.938T>C | p.Val313Ala | missense_variant, splice_region_variant | 10/16 | ENST00000209873.9 | |
AAAS | NM_001173466.2 | c.839T>C | p.Val280Ala | missense_variant, splice_region_variant | 9/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AAAS | ENST00000209873.9 | c.938T>C | p.Val313Ala | missense_variant, splice_region_variant | 10/16 | 1 | NM_015665.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152024Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461894Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152024Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74236
ClinVar
Submissions by phenotype
Glucocorticoid deficiency with achalasia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2022 | Variant summary: AAAS c.938T>C (p.Val313Ala) results in a non-conservative amino acid change located in the WD-repeat domain (Cronshaw_2003) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251494 control chromosomes. c.938T>C has been reported in the literature as a biallelic genotype in individuals affected with Glucocorticoid Deficiency With Achalasia (AAA syndrome) (example, Houlden_2002, de Freitas_2018). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function reporting subcellular mislocalization of the mutant proteins within the cytoplasm (example, Krumbholz_2006, Cronshaw_2003). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Mendelics | May 13, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at