rs398122368

Positions:

• chr22-23791772-G-A
• chr22-23791772-G-C
• chr22-23791772-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:2
• Conservation: PhyloP100: 9.70

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest DNA-binding (size 112) in uniprot entity SNF5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003073.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCB1. . Gene score misZ 3.6016 (greater than the threshold 3.09). Trascript score misZ 4.8554 (greater than threshold 3.09). GenCC has associacion of gene with schwannomatosis 1, familial multiple meningioma, rhabdoid tumor predisposition syndrome 1, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 15, familial rhabdoid tumor, schwannomatosis, Coffin-Siris syndrome.
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 88893.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=4}. Variant chr22-23791772-G-A is described in Lovd as [Pathogenic]. Variant chr22-23791772-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.110G>A	p.Arg37His	missense_variant	2/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.110G>A	p.Arg37His	missense_variant	2/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.110G>A	p.Arg37His	missense_variant	2/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.110G>A	p.Arg37His	missense_variant	2/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.110G>A	p.Arg37His	missense_variant	2/9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:4 Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2021	- -
Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Sep 01, 2017	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, University of Torino	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29907796, 22726846, 25168959) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

SMARCB1-related BAFopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

Coffin-Siris syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

May 16, 2024

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	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
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	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.
PrimateAI	Pathogenic	0.91	D
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	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs398122368; hg19: chr22-24133959;