rs137852305
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000032.5(ALAS2):c.1231C>T(p.Arg411Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R411H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000032.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALAS2 | NM_000032.5 | c.1231C>T | p.Arg411Cys | missense_variant | 9/11 | ENST00000650242.1 | NP_000023.2 | |
ALAS2 | NM_001037968.4 | c.1192C>T | p.Arg398Cys | missense_variant | 9/11 | NP_001033057.1 | ||
ALAS2 | NM_001037967.4 | c.1120C>T | p.Arg374Cys | missense_variant | 8/10 | NP_001033056.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALAS2 | ENST00000650242.1 | c.1231C>T | p.Arg411Cys | missense_variant | 9/11 | NM_000032.5 | ENSP00000497236.1 | |||
ALAS2 | ENST00000396198.7 | c.1192C>T | p.Arg398Cys | missense_variant | 9/11 | 5 | ENSP00000379501.3 | |||
ALAS2 | ENST00000335854.8 | c.1120C>T | p.Arg374Cys | missense_variant | 8/10 | 2 | ENSP00000337131.4 | |||
ALAS2 | ENST00000498636.1 | c.520C>T | p.Arg174Cys | missense_variant | 4/5 | 3 | ENSP00000495662.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 411 of the ALAS2 protein (p.Arg411Cys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALAS2 function (PMID: 9858242, 21309041). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. ClinVar contains an entry for this variant (Variation ID: 10475). This missense change has been observed in individuals with sideroblastic anemia (PMID: 7592563, 9858242, 32297424). - |
X-linked sideroblastic anemia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at