rs775057827
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_014140.4(SMARCAL1):āc.836T>Cā(p.Phe279Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,613,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. F279F) has been classified as Likely benign.
Frequency
Consequence
NM_014140.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCAL1 | NM_014140.4 | c.836T>C | p.Phe279Ser | missense_variant | 4/18 | ENST00000357276.9 | |
SMARCAL1 | NM_001127207.2 | c.836T>C | p.Phe279Ser | missense_variant | 4/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCAL1 | ENST00000357276.9 | c.836T>C | p.Phe279Ser | missense_variant | 4/18 | 2 | NM_014140.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251494Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135922
GnomAD4 exome AF: 0.0000746 AC: 109AN: 1461538Hom.: 1 Cov.: 30 AF XY: 0.0000756 AC XY: 55AN XY: 727090
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 04, 2023 | The SMARCAL1 c.836T>C variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM3, PP3) The SMARCAL1 c.836T>C variant is a single nucleotide change in exon 4/18 of the SMARCAL1 gene, which is predicted to change the amino acid phenylalanine at position 279 in the protein to serine. The variant has been reported in >5 affected patients in the literature (PMID:17089404, PMID:21914180, PMID:22998683, PMID:26499378, PMID:30295827) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.0059%; 9 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.010%, Non-Finnish European population) (PM2). This variant has been detected in trans with a pathogenic variant for this recessive condition (PMID:22998683, PMID:15880370, 30295827) (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs775057827) and in the HGMD database as disease causing (CM051640). It has been reported as uncertain significance and likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 562357). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 279 of the SMARCAL1 protein (p.Phe279Ser). This variant is present in population databases (rs775057827, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Schimke immunoosseous dysplasia (PMID: 15880370, 15884045, 17089404, 21914180, 22998683, 26499378, 30586318). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562357). 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 SMARCAL1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 03, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 26, 2022 | - - |
not provided Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at