rs119473038
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_014140.4(SMARCAL1):c.1756C>T(p.Arg586Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,607,756 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. R586Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_014140.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCAL1 | NM_014140.4 | c.1756C>T | p.Arg586Trp | missense_variant | 11/18 | ENST00000357276.9 | |
SMARCAL1 | NM_001127207.2 | c.1756C>T | p.Arg586Trp | missense_variant | 11/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCAL1 | ENST00000357276.9 | c.1756C>T | p.Arg586Trp | missense_variant | 11/18 | 2 | NM_014140.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000137 AC: 2AN: 145970Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251000Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135678
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461786Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727206
GnomAD4 genome ? AF: 0.0000137 AC: 2AN: 145970Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1AN XY: 71272
ClinVar
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 586 of the SMARCAL1 protein (p.Arg586Trp). This variant is present in population databases (rs119473038, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Schimke immunoosseous dysplasia (PMID: 11799392, 29127259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4176). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
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