rs398122368

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_003073.5(SMARCB1):c.110G>A(p.Arg37His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCB1
NM_003073.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:2

Conservation

PhyloP100: 9.70

Publications

11 publications found

Variant links:

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
intellectual disability, autosomal dominant 15
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
rhabdoid tumor predisposition syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
SMARCB1-related schwannomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
familial multiple meningioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schwannomatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SMARCB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003073.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-23791771-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3363753.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

PP5

Variant 22-23791772-G-A is Pathogenic according to our data. Variant chr22-23791772-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 9	ENST00000644036.2	NP_003064.2	Q12824-1
SMARCB1	NM_001362877.2 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 9		NP_001349806.1
SMARCB1	NM_001317946.2 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 9		NP_001304875.1	G5E975Q9H836
SMARCB1	NM_001007468.3 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 9		NP_001007469.1	Q12824-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 9		NM_003073.5	ENSP00000494049.2		Q12824-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000258

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 15

Pathogenic:5Uncertain:2

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are all known mechanisms of disease in this gene. Loss of function variants are associated with cancer susceptibility (rhabdoid tumor predisposition syndrome 1 (MIM#609322), schwannomatosis-1 (MIM#162091), rhabdoid tumors somatic (MIM#609322)). An inframe deletion variant, missense variants and truncating variants escaping nonsense-mediated decay have all been reported to have either a gain of function or dominant negative mechanism, and are associated with Coffin-Siris syndrome 3 (MIM#614608) (OMIM, PMID: 31759698). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in gnomAD). This variant is located in the DNA binding domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been observed de novo in multiple affected individuals (PMIDs: 29907796, 34906496, 31172278). In addition, it has been reported as pathogenic and likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 13, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PM2, PM5, PP3 -

Sep 01, 2017

Baylor Genetics

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in a 6-year-old male with global delays, autism spectrum, hypotonia, hydrocephalus, VUR, agenesis of the corpus callosum, myopia, pes cavus, elevated free T4; in an 8-year-old female with intellectual disability, behavior problems, hydrocephalus, dysmorphisms, amblyopia, myopic astigmatixm, hypoplastic labia majora, hypertonia, decreased muscle mass, dysphagia, Wilms tumor -

Laboratory of Medical Genetics, University of Torino

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Coffin-Siris syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/22726846). -

not provided

Pathogenic:2

Jun 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29907796, 22726846, 25168959, 34906496, 36964972, 33057194, 35982159, 26073604) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SMARCB1-related BAFopathy

Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Coffin-Siris syndrome

Pathogenic:1

May 16, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous p.Arg37His variant in SMARCB1 was identified by our study in one individual with Coffin-Siris syndrome. The p.Arg37His variant in SMARCB1 has been reported in >10 individuals with Coffin-Siris syndrome (PMIDs: 22726846, 29907796, 33057194, 34906496, 36964972), but was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has been reported in ClinVar (Variation ID: 88893) and has been interpreted as uncertain significance by two submitters, likely pathogenic by two submitters, and pathogenic by three submitters. This variant is assumed de novo in 11 individuals, but maternity and paternity have not been confirmed (PMIDs: 22726846, 29907796, 34906496, 36964972). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in SMARCB1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Coffin-Siris syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Moderate, PP2, PM6, PP3_Moderate (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;D;T;.;.;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;.;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.1

M;M;.;.;.;.

PhyloP100

9.7

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.4

N;.;N;N;N;N

REVEL

Pathogenic

0.80

Sift

Benign

0.15

T;.;T;T;T;T

Sift4G

Benign

0.074

T;.;T;T;T;T

Polyphen

0.89, 0.41, 1.0

.;P;B;.;.;D

Vest4

0.69

MutPred

0.54

Loss of MoRF binding (P = 0.0111);Loss of MoRF binding (P = 0.0111);Loss of MoRF binding (P = 0.0111);Loss of MoRF binding (P = 0.0111);Loss of MoRF binding (P = 0.0111);Loss of MoRF binding (P = 0.0111);

MVP

0.97

MPC

1.9

ClinPred

0.96

GERP RS

5.6

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.95

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over