rs267607072

Positions:

• chr22-23787261-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong 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:1
• 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 Pathogenic. Variant got 10 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• 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: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	1/9		NP_001349806.1
SMARCB1	NM_001317946.2	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	1/9		NP_001304875.1
SMARCB1	NM_001007468.3	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	1/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.92A>T	p.Glu31Val	missense_variant, splice_region_variant	1/9		NM_003073.5	ENSP00000494049	A1

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:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	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. -

Schwannomatosis 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

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;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
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;