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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 6.34

Variant links:

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]

SMARCAL1 links:

Genome browser will be placed here

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 link	c.2542G>T	p.Glu848*	stop_gained	Exon 17 of 18	ENST00000357276.9	NP_054859.2	Q9NZC9
SMARCAL1	NM_001127207.2 link	c.2542G>T	p.Glu848*	stop_gained	Exon 17 of 18		NP_001120679.1	Q9NZC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 link	c.2542G>T	p.Glu848*	stop_gained	Exon 17 of 18	2	NM_014140.4	ENSP00000349823.4		Q9NZC9

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251422

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.0000827

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000125

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

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

Jan 27, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 21, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 26, 2017

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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%). -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Institute of Human Genetics, Cologne University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCAL1: PVS1, PM2 -

Dec 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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

Mar 04, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome

Pathogenic:1

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

Vest4

0.82

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over