chr22-23787261-A-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_003073.5(SMARCB1):​c.92A>T​(p.Glu31Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000696 in 1,435,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 6.22

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 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 22-23787261-A-T is Pathogenic according to our data. Variant chr22-23787261-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8031.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	Exon 1 of 9		NP_001349806.1
SMARCB1	NM_001317946.2	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	Exon 1 of 9		NP_001304875.1
SMARCB1	NM_001007468.3	c.92A>T	p.Glu31Val	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>T	p.Glu31Val	missense_variant, splice_region_variant	Exon 1 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435876 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 715416

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: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Dec 05, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Published functional studies suggest this variant likely results in a nulle allele (Bacci et al., 2010); This variant is associated with the following publications: (PMID: 26073604, 31586052, 19582488) -

Nov 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 31 of the SMARCB1 protein (p.Glu31Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with schwannomatosis (PMID: 19582488, 22434358). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8031). 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 alters SMARCB1 gene expression (PMID: 19582488). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

SMARCB1-related schwannomatosis Pathogenic:1

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E31V variant (also known as c.92A>T), located in coding exon 1 of the SMARCB1 gene, results from an A to T substitution at nucleotide position 92. The glutamic acid at codon 31 is replaced by valine, an amino acid with dissimilar properties. This variant was identified in one or more individuals with features consistent with schwannomatosis and segregated with disease in at least one family (Bacci C et al. Neurogenetics, 2010 Feb;11:73-80). 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 available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D;T;.;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;.;.;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;.;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D;D;D
Polyphen		0.99, 0.97, 0.61	.;D;D;.;.;P
Vest4		0.73
MutPred		0.58		Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);Gain of MoRF binding (P = 0.0433);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.85
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		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: rs267607072; hg19: chr22-24129448;