chr19-11021737-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001387283.1(SMARCA4):c.2629T>G(p.Tyr877Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y877H) 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: 8.02

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001387283.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 20 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 19 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.2629T>G	p.Tyr877Asp	missense_variant	Exon 20 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.2041T>G	p.Tyr681Asp	missense_variant	Exon 16 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.1273T>G	p.Tyr425Asp	missense_variant	Exon 12 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.1354T>G	p.Tyr452Asp	missense_variant	Exon 12 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.1114T>G	p.Tyr372Asp	missense_variant	Exon 11 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.982T>G	p.Tyr328Asp	missense_variant	Exon 10 of 25			ENSP00000494159.1

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

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Apr 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This sequence change replaces tyrosine with aspartic acid at codon 877 of the SMARCA4 protein (p.Tyr877Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-8.9

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

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.93

MutPred

0.83

Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);.;Gain of disorder (P = 0.0499);.;.;.;.;

MVP

0.99

MPC

5.0

ClinPred

1.0

GERP RS

4.7

PromoterAI

0.053

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.98

gMVP

1.0

Mutation Taster

=9/91

disease causing

(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