rs119473033
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014140.4(SMARCAL1):c.2542G>T(p.Glu848*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000083 in 1,614,152 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014140.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251422Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135900
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727226
GnomAD4 genome AF: 0.000125 AC: 19AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74482
ClinVar
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:11
- -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. -
- -
PVS1: The c.2542G>T (p.Glu848Ter) variant is a stop gained variant and is predicted to result in premature truncation of the protein. The p.Glu848Ter variant has been reported many times in patients (PMID: 24589093, PMID: 11799392). Functional studies showed that the p.Glu848Ter variant results in undetectable protein levels, protein mislocalization, and deficient ATP hydrolyzation (PMID: 18805831). PM2: Rare in reference population databases, gnomAD AC = 24 (Finnish AF = 0.02%). -
The SMARCAL1 c.2542G>T (p.Glu848Ter) variant is a stop gained variant and is predicted to result in premature truncation of the protein. The p.Glu848Ter variant has been reported in at least seven studies in which it is found a total of 28 individuals with Schimke immunoosseous dysplasia, including 11 in a homozygous state and 17 in a compound heterozygous state (Boerkoel et al. 2002; Clewing et al. 2007a; Clewing et al. 2007b; Zivicnjak et al. 2009; Zieg et al. 2011; Santangelo et al. 2014; Sanyal et al. 2015). The p.Glu848Ter variant has also been reported in a heterozygous state in nine unaffected parents (Boerkoel et al. 2002; Zieg et al. 2011; Santangelo et al. 2014). The variant was absent from 126 control chromosomes but is reported at a frequency of 0.00045 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Glu848Ter variant results in undetectable protein levels, protein mislocalization, and deficient ATP hydrolyzation (Elizondo et al. 2009). Based on the potential impact of stop-gained variants and the collective evidence, the p.Glu848Ter variant is classified as pathogenic for Schimke immunoosseous dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
- -
- -
- -
- -
This sequence change creates a premature translational stop signal (p.Glu848*) in the SMARCAL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCAL1 are known to be pathogenic (PMID: 11799392, 20301550). This variant is present in population databases (rs119473033, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Schimke-immuno-osseous dysplasia (PMID: 11799392, 15880370, 18805831, 19127206, 22998683, 26499378, 28796785). ClinVar contains an entry for this variant (Variation ID: 4171). For these reasons, this variant has been classified as Pathogenic. -
The SMARCAL1 (p.Glu848*) nonsense variant is predicted to result in nonsense-mediated decay or premature protein termination. This variant was reported in the compound heterozygous state in families with Schimke-immuno-osseous dysplasia (PMID: 15880370; 11799392; 28796785). -
not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 32115305, 31980526, 31589614, 17089404, 15880370, 21914180, 28796785, 19127206, 34503567, 11799392, 24589093, 29282041, 29127259, 18805831) -
SMARCAL1: PVS1, PM2 -
Focal segmental glomerulosclerosis;C0235991:Small for gestational age;C0349588:Short stature;C0403397:Steroid-resistant nephrotic syndrome;C1846435:Disproportionate short-trunk short stature;C2677180:Primary microcephaly;C4551563:Microcephaly;C5574742:Decreased body weight;CN029142:Familial atrioventricular septal defect Pathogenic:1
- -
Nephrotic syndrome Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at