19-10986236-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003072.5(SMARCA4):c.403C>T(p.Pro135Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.26

Variant links:

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.11807376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 5 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 4 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.403C>T	p.Pro135Ser	missense_variant	Exon 5 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.-186C>T		upstream_gene_variant				ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248640

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134712

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:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727160

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 135 of the SMARCA4 protein (p.Pro135Ser). This variant is present in population databases (rs150949949, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1425107). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 01, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P135S variant (also known as c.403C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 403. The proline at codon 135 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Benign

0.076

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.71

DEOGEN2

Benign

0.34

T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

.;D;.;.;.;.;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

-0.69

N;.;.;.;N;N;.;N;N;N;N;.;N;N;N;N;N;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.4

N;.;.;.;.;.;.;.;.;.;N;.;.;N;.;N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.59

T;.;.;.;.;.;.;.;.;.;T;.;.;T;.;T;.;T;T

Sift4G

Benign

0.28

T;.;.;.;.;.;.;.;.;.;T;.;.;T;T;T;T;T;T

Polyphen

0.0010

B;.;D;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;D

Vest4

0.31

MutPred

0.17

Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);Gain of phosphorylation at P135 (P = 0.0047);

MVP

0.58

MPC

0.89

ClinPred

0.039

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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