chr22-50626878-C-G
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_000487.6(ARSA):āc.640G>Cā(p.Ala214Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,108 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214V) has been classified as Pathogenic.
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.640G>C | p.Ala214Pro | missense_variant | 3/8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.640G>C | p.Ala214Pro | missense_variant | 3/8 | 1 | NM_000487.6 | ENSP00000216124.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461108Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726834
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 14, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 214 of the ARSA protein (p.Ala214Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133). This variant is also known as p.Ala212Pro. ClinVar contains an entry for this variant (Variation ID: 68145). 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. Experimental studies have shown that this missense change affects ARSA function (PMID: 18693274, 19606494). This variant disrupts the p.Ala214 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7906588, 9090526, 9192271, 14517960, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 27, 2021 | - - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
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