rs267607072

Variant names:

• chr22-23787261-A-G
• rs267607072
• NM_003073.5:c.92A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-23787261-A-G
• chr22-23787261-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003073.5(SMARCB1):​c.92A>G​(p.Glu31Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E31V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCB1 NM_003073.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.22
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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, 23 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 chr22-23787261-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8031.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 22-23787261-A-G is Pathogenic according to our data. Variant chr22-23787261-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2764125.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	Exon 1 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	Exon 1 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	Exon 1 of 9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.92A>G	p.Glu31Gly	missense_variant, splice_region_variant	Exon 1 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 31 of the SMARCB1 protein (p.Glu31Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with schwannomatosis (PMID: 36363549; Invitae). 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. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;T;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;.;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;.;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D;.;D;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;D;D
Polyphen		0.99, 0.97, 0.61	.;D;D;.;.;P
Vest4		0.63
MutPred		0.46		Gain of glycosylation at S30 (P = 0.0377);Gain of glycosylation at S30 (P = 0.0377);Gain of glycosylation at S30 (P = 0.0377);Gain of glycosylation at S30 (P = 0.0377);Gain of glycosylation at S30 (P = 0.0377);Gain of glycosylation at S30 (P = 0.0377);
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		-0.14	Neutral
Varity_R		0.78
gMVP		0.99
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267607072; hg19: chr22-24129448;