rs373041389

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387283.1(SMARCA4):c.3894C>A(p.Asp1298Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1298N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.73

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

ENSG00000278643 (HGNC:):

ENSG00000278643 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.3894C>A	p.Asp1298Glu	missense_variant	Exon 28 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3894C>A	p.Asp1298Glu	missense_variant	Exon 28 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.3894C>A	p.Asp1298Glu	missense_variant	Exon 28 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.3894C>A	p.Asp1298Glu	missense_variant	Exon 28 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.3795C>A	p.Asp1265Glu	missense_variant	Exon 27 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.3795C>A	p.Asp1265Glu	missense_variant	Exon 28 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.3795C>A	p.Asp1265Glu	missense_variant	Exon 27 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.3795C>A	p.Asp1265Glu	missense_variant	Exon 27 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.3795C>A	p.Asp1265Glu	missense_variant	Exon 28 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.3306C>A	p.Asp1102Glu	missense_variant	Exon 25 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.2538C>A	p.Asp846Glu	missense_variant	Exon 21 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.2520C>A	p.Asp840Glu	missense_variant	Exon 20 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.2379C>A	p.Asp793Glu	missense_variant	Exon 20 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.2247C>A	p.Asp749Glu	missense_variant	Exon 19 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.51C>A	p.Asp17Glu	missense_variant	Exon 2 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 08, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D1298E variant (also known as c.3894C>A), located in coding exon 27 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 3894. The aspartic acid at codon 1298 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

1.5

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

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

Eigen

Benign

0.035

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.8

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

PhyloP100

-1.7

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.58

MutPred

0.30

Loss of phosphorylation at T1301 (P = 0.217);.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;.;.;.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;.;.;Loss of phosphorylation at T1301 (P = 0.217);.;.;.;.;

MVP

0.89

MPC

2.6

ClinPred

0.96

GERP RS

0.86

PromoterAI

0.0030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.40

gMVP

0.84

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over