rs119473033
Variant names:
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
Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000079 ( 0 hom. )
Consequence
SMARCAL1
NM_014140.4 stop_gained
NM_014140.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.34
Genes affected
SMARCAL1 (HGNC:11102): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-216478216-G-T is Pathogenic according to our data. Variant chr2-216478216-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 4171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-216478216-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251422Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135900
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GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727226
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GnomAD4 genome 0.000125 AC: 19AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74482
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Schimke immuno-osseous dysplasia Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 30, 2024 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2024 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 27, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Aug 21, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 10, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | 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). - |
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jun 26, 2017 | 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%). - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 04, 2014 | - - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at