19-11059795-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001387283.1(SMARCA4):c.4774G>T(p.Val1592Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000224 in 1,607,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. V1592M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.67

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17329806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4774G>T	p.Val1592Leu	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4678G>T	p.Val1560Leu	missense_variant	Exon 33 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.4774G>T	p.Val1592Leu	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.4678G>T	p.Val1560Leu	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.4684G>T	p.Val1562Leu	missense_variant	Exon 33 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.4588G>T	p.Val1530Leu	missense_variant	Exon 33 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.4588G>T	p.Val1530Leu	missense_variant	Exon 32 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.4588G>T	p.Val1530Leu	missense_variant	Exon 32 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.4585G>T	p.Val1529Leu	missense_variant	Exon 33 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.4099G>T	p.Val1367Leu	missense_variant	Exon 30 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.3328G>T	p.Val1110Leu	missense_variant	Exon 26 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.3310G>T	p.Val1104Leu	missense_variant	Exon 25 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.3172G>T	p.Val1058Leu	missense_variant	Exon 25 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.2938G>T	p.Val980Leu	missense_variant	Exon 23 of 25			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 link	c.742G>T	p.Val248Leu	missense_variant	Exon 6 of 8	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

234874

AF XY:

0.0000157

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1454992

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

43540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25950

East Asian (EAS)

AF:

0.00

AC:

AN:

39348

South Asian (SAS)

AF:

0.00

AC:

AN:

85144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000289

AC:

AN:

1108832

Other (OTH)

AF:

0.0000166

AC:

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68054

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Uncertain:2

Feb 22, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Mar 29, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1592 of the SMARCA4 protein (p.Val1592Leu). This variant is present in population databases (rs374983142, gnomAD 0.004%). 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: 238483). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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

Benign:1

Mar 25, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

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

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

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

PhyloP100

4.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.74

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

REVEL

Benign

0.13

Sift

Benign

0.24

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

Sift4G

Benign

0.26

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

Polyphen

0.0020

B;.;P;.;.;.;.;.;.;.;B;.;.;.;.;.;.;P;.;.;.;.

Vest4

0.21

MutPred

0.27

.;.;Loss of helix (P = 0.1706);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.1706);.;.;.;.;

MVP

0.47

MPC

0.97

ClinPred

0.31

GERP RS

4.0

Varity_R

0.27

gMVP

0.95

Mutation Taster

=74/26

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over