rs267607071
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_014140.4(SMARCAL1):c.2291G>A(p.Arg764Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,076 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. R764W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014140.4 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 |
---|---|---|---|---|---|---|---|
SMARCAL1 | NM_014140.4 | c.2291G>A | p.Arg764Gln | missense_variant | 15/18 | ENST00000357276.9 | |
SMARCAL1 | NM_001127207.2 | c.2291G>A | p.Arg764Gln | missense_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCAL1 | ENST00000357276.9 | c.2291G>A | p.Arg764Gln | missense_variant | 15/18 | 2 | NM_014140.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251310Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135840
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 764 of the SMARCAL1 protein (p.Arg764Gln). This variant is present in population databases (rs267607071, gnomAD 0.006%). This missense change has been observed in individual(s) with Schimke immuno-osseous dysplasia (PMID: 11799392, 22998683). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4178). 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 SMARCAL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SMARCAL1 function (PMID: 18805831, 18974355, 19793864, 23671665, 26089390). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2009 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at