rs387906812

chr22-23834152-G-Achr22-23834152-G-Cchr22-23834152-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_003073.5(SMARCB1):c.1130G>A(p.Arg377His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,593,918 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMARCB1
NM_003073.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 9.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 3 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 chr22-23834151-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 638627.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant where missense usually causes diseases, SMARCB1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 22-23834152-G-A is Pathogenic according to our data. Variant chr22-23834152-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30203.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr22-23834152-G-A is described in UniProt as null. Variant chr22-23834152-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SMARCB1	NM_003073.5 linkuse as main transcript	c.1130G>A	p.Arg377His	missense_variant	9/9	ENST00000644036.2
SMARCB1	NM_001362877.2 linkuse as main transcript	c.1184G>A	p.Arg395His	missense_variant	9/9
SMARCB1	NM_001317946.2 linkuse as main transcript	c.1157G>A	p.Arg386His	missense_variant	9/9
SMARCB1	NM_001007468.3 linkuse as main transcript	c.1103G>A	p.Arg368His	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2 linkuse as main transcript	c.1130G>A	p.Arg377His	missense_variant	9/9		NM_003073.5	A1	Q12824-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 15

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 18, 2012

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 22426308, 25169651). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30203). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 377 of the SMARCB1 protein (p.Arg377His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2018

PLEASE SELECT CORRECT RD FOR YOUR CASE - EDIT IN THE REPORT VUS (CANCER) The p.R377H variant (also known as c.1130G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in patients with Coffin-Siris syndrome and DOORS syndrome (Tsurusaki Y et al. Nat. Genet. 2012 Mar;44:376-8; Kosho T et al. Am. J. Med. Genet. A. 2013 Jun;161A:1221-37; Campeau PM et al. Am. J. Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:327-32; Kosho T et al. Am. J Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:262-75). It has also been identified as a somatic variant in multiple tumor types including meningiomas (Schmitz U et al. Br. J. Cancer. 2001 Jan;84:199-201; Torres-Martín M et al. Cancer Genet. 2015 Jun;208:327-32; Tang M et al. Oncotarget. 2017 Mar;8:17070-17080), gastric cancers (Kim JG et al. Cancer Lett. 2013 Mar;330:33-40; Takeshima H et al. Cancer Lett., 2015 Feb;357:328-338), odontogenic tumors (Brown NA et al. Clin. Cancer Res. 2014 Nov;20:5517-26), sarcomas (Andersson C et al. Cancer Genet, 2016 Apr;209:154-60), and schwannomas (Paganini I et al. J. Neurooncol. 2018 Mar;137:33-38). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear for hereditary cancer predisposition . VLP (NEURO) The p.R377H variant (also known as c.1130G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected de novo in an individual with Coffin-Siris syndrome (Tsurusaki Y et al. Nat. Genet. 2012 Mar;44:376-8; Kosho T et al. Am. J. Med. Genet. A. 2013 Jun;161A:1221-37; Kosho T et al. Am. J Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:262-75). This variant was also detected de novo in two individuals with DOORS syndrome (Campeau PM et al. Am. J. Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:327-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.6

D;.;D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0030

D;.;D;.

Polyphen

1.0

.;D;D;.

Vest4

0.81

MutPred

0.46

.;.;Loss of helix (P = 0.0304);.;

MVP

0.98

MPC

2.8

ClinPred

0.99

GERP RS

5.1

Varity_R

0.82

gMVP

0.98

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