rs1057517825

Positions:

• chr22-23834143-G-A
• chr22-23834143-G-C
• chr22-23834143-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_003073.5(SMARCB1):​c.1121G>A​(p.Arg374Gln) variant causes a missense, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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. R374W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCB1 NM_003073.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.63

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 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 chr22-23834142-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 633561.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, SMARCB1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-23834143-G-A is Pathogenic according to our data. Variant chr22-23834143-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372511.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr22-23834143-G-A is described in UniProt as null. Variant chr22-23834143-G-A is described in Lovd as [Pathogenic]. Variant chr22-23834143-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCB1	NM_003073.5	c.1121G>A	p.Arg374Gln	missense_variant, splice_region_variant	9/9	ENST00000644036.2
SMARCB1	NM_001362877.2	c.1175G>A	p.Arg392Gln	missense_variant, splice_region_variant	9/9
SMARCB1	NM_001317946.2	c.1148G>A	p.Arg383Gln	missense_variant, splice_region_variant	9/9
SMARCB1	NM_001007468.3	c.1094G>A	p.Arg365Gln	missense_variant, splice_region_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCB1	ENST00000644036.2	c.1121G>A	p.Arg374Gln	missense_variant, splice_region_variant	9/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438640 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 713658

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 15 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	Reported in an adult male in published literature with Coffin-Siris syndrome and schwannomatosis (Gossai et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11104031, 23091298, 23525077, 31216405, 23906836, 31273213, 26364901) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the SMARCB1 protein (p.Arg374Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 23906836, 26364901, 31273213; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372511). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

SMARCB1-related BAFopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2017

The p.R374Q variant (also known as c.1121G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with Coffin-Siris syndrome (Wieczorek D et al. Hum. Mol. Genet., 2013 Dec;22:5121-35; Kosho T et al. Am J Med Genet C Semin Med Genet, 2014 Sep;166C:262-75; Gossai N et al. Am. J. Med. Genet. A, 2015 Dec;167A:3186-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Pathogenic	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;.;D;.
Sift4G	Uncertain	0.0060	D;.;D;.
Polyphen		1.0	.;D;D;.
Vest4		0.82
MutPred		0.40		.;.;Gain of relative solvent accessibility (P = 0.2751);.;
MVP		0.99
MPC		2.7
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517825; hg19: chr22-24176330; COSMIC: COSV51954334; COSMIC: COSV51954334;