19-11059781-C-T

Variant names:

Variant summary

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

The NM_001387283.1(SMARCA4):c.4760C>T(p.Ser1587Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000689 in 1,596,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1587T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 6.01

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4760C>T	p.Ser1587Leu	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4664C>T	p.Ser1555Leu	missense_variant	Exon 33 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.4760C>T	p.Ser1587Leu	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.4664C>T	p.Ser1555Leu	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.4670C>T	p.Ser1557Leu	missense_variant	Exon 33 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.4574C>T	p.Ser1525Leu	missense_variant	Exon 33 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.4574C>T	p.Ser1525Leu	missense_variant	Exon 32 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.4574C>T	p.Ser1525Leu	missense_variant	Exon 32 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.4571C>T	p.Ser1524Leu	missense_variant	Exon 33 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.4085C>T	p.Ser1362Leu	missense_variant	Exon 30 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.3314C>T	p.Ser1105Leu	missense_variant	Exon 26 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.3296C>T	p.Ser1099Leu	missense_variant	Exon 25 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.3158C>T	p.Ser1053Leu	missense_variant	Exon 25 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.2924C>T	p.Ser975Leu	missense_variant	Exon 23 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.728C>T	p.Ser243Leu	missense_variant	Exon 6 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000919

AC:

AN:

217648

AF XY:

0.0000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000692

AC:

AN:

1444514

Hom.:

Cov.:

AF XY:

0.00000976

AC XY:

AN XY:

717168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.0000242

AC:

AN:

41346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25746

East Asian (EAS)

AF:

0.00

AC:

AN:

38766

South Asian (SAS)

AF:

0.00

AC:

AN:

83700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000815

AC:

AN:

1103932

Other (OTH)

AF:

0.00

AC:

AN:

59812

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

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:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Nov 17, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1587 of the SMARCA4 protein (p.Ser1587Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 391153). 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) indicates that this missense variant is expected to disrupt SMARCA4 protein function with a positive predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Intellectual disability, autosomal dominant 16

Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 14, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The S1587L variant in the SMARCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S1587L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1587L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.4760 C>T (aka S1587L) might create a cryptic splice acceptor site in exon 34 which may supplant the natural acceptor site. However, in the absence of RNA/functional studies, the actual effect of c.4760 C>T in this individual is unknown. We interpret S1587L as a variant of uncertain significance. -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12

Uncertain:1

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 27, 2023

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

Pathogenic

0.98

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.42

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

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

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

PhyloP100

6.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.0

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

REVEL

Benign

0.19

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.041

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

Polyphen

0.99

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

Vest4

0.87

MutPred

0.29

.;.;Loss of disorder (P = 0.064);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.064);.;.;.;.;

MVP

0.58

MPC

1.9

ClinPred

0.96

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.85

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over