chr22-50626204-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000487.6(ARSA):c.929G>A(p.Gly310Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G310C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.929G>A | p.Gly310Asp | missense_variant | 5/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.929G>A | p.Gly310Asp | missense_variant | 5/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460010Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726178
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2023 | This variant disrupts the p.Gly310 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 8891236, 10477432; Invitae), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 310 of the ARSA protein (p.Gly310Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 10477432; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly308Asp. ClinVar contains an entry for this variant (Variation ID: 68163). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at