rs762676176

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_003073.5(SMARCB1):c.79A>C(p.Met27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SMARCB1
NM_003073.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.97

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SMARCB1	NM_003073.5 linkuse as main transcript	c.79A>C	p.Met27Leu	missense_variant	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2 linkuse as main transcript	c.79A>C	p.Met27Leu	missense_variant	1/9		NP_001349806.1
SMARCB1	NM_001317946.2 linkuse as main transcript	c.79A>C	p.Met27Leu	missense_variant	1/9		NP_001304875.1
SMARCB1	NM_001007468.3 linkuse as main transcript	c.79A>C	p.Met27Leu	missense_variant	1/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 linkuse as main transcript	c.79A>C	p.Met27Leu	missense_variant	1/9		NM_003073.5	ENSP00000494049	A1	Q12824-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

244006

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449104

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721572

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:

0.00000363

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 15, 2023

- -

Intellectual disability, autosomal dominant 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 13, 2019

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2023

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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 464339). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This variant is present in population databases (rs762676176, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 27 of the SMARCB1 protein (p.Met27Leu). -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The p.M27L variant (also known as c.79A>C), located in coding exon 1 of the SMARCB1 gene, results from an A to C substitution at nucleotide position 79. The methionine at codon 27 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Missense and in-frame variants in SMARCB1 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, the association of this alteration with SMARCB1-related tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Uncertain

0.49

.;T;T;.;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.052

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;.;.;.;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.43

T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.9

L;L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.1

N;.;N;N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.46

T;.;T;T;T;T

Sift4G

Benign

1.0

T;.;T;T;T;T

Polyphen

0.10, 0.0010, 0.0

.;B;B;.;.;B

Vest4

0.64

MutPred

0.34

Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);Loss of phosphorylation at Y26 (P = 0.0906);

MVP

0.78

MPC

1.2

ClinPred

0.95

GERP RS

2.4

Varity_R

0.62

gMVP

0.92

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