rs1555762188

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_003072.5(SMARCA4):c.1583G>A(p.Arg528Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.97

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 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.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 10 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 9 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.1583G>A	p.Arg528Gln	missense_variant	Exon 10 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.995G>A	p.Arg332Gln	missense_variant	Exon 6 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.227G>A	p.Arg76Gln	missense_variant	Exon 2 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.311G>A	p.Arg104Gln	missense_variant	Exon 2 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.71G>A	p.Arg24Gln	missense_variant	Exon 1 of 27			ENSP00000495355.1	A0A2R8Y6N0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459460

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725806

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glutamine at codon 528 of the SMARCA4 protein (p.Arg528Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R528Q variant (also known as c.1583G>A), located in coding exon 8 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1583. The arginine at codon 528 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.50

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.8

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

REVEL

Benign

0.16

Sift

Benign

0.74

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

Sift4G

Benign

0.66

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

Polyphen

0.94

P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.

Vest4

0.54

MutPred

0.47

Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);Loss of MoRF binding (P = 0.0285);.;.;

MVP

0.65

MPC

1.9

ClinPred

0.98

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.97

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