rs1480919035
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_014140.4(SMARCAL1):c.2290C>T(p.Arg764Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,080 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R764Q) has been classified as Pathogenic.
Frequency
Consequence
NM_014140.4 missense
Scores
Clinical Significance
Conservation
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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.2290C>T | p.Arg764Trp | missense_variant | 15/18 | ENST00000357276.9 | |
SMARCAL1 | NM_001127207.2 | c.2290C>T | p.Arg764Trp | missense_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCAL1 | ENST00000357276.9 | c.2290C>T | p.Arg764Trp | missense_variant | 15/18 | 2 | NM_014140.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2021 | This variant has been observed in individual(s) with clinical features of Schimke immuno-osseous dysplasia or steroid-resistant nephrotic syndrome (PMID: 28796785, 29127259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495338). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 764 of the SMARCAL1 protein (p.Arg764Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant disrupts the p.Arg764 amino acid residue in SMARCAL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11799392, 22998683, 18974355, 18805831). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jun 26, 2017 | No reports in the literature identified for this variant. Seen as homozygous variant in 1 case in CMG with nephrotic syndrome. PM2: rare in reference population databases with AC=1 in gnomAD. PP3: In silico predicts damaging. - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at