rs759192892

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001387283.1(SMARCA4):c.3703G>A(p.Asp1235Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.61

Publications

4 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 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001387283.1

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.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 27 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 26 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.3703G>A	p.Asp1235Asn	missense_variant	Exon 27 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.3115G>A	p.Asp1039Asn	missense_variant	Exon 23 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.2347G>A	p.Asp783Asn	missense_variant	Exon 19 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.2428G>A	p.Asp810Asn	missense_variant	Exon 19 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.2188G>A	p.Asp730Asn	missense_variant	Exon 18 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.2056G>A	p.Asp686Asn	missense_variant	Exon 17 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.-42G>A		upstream_gene_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251040

AF XY:

0.00000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60384

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

Cov.:

ExAC

AF:

0.0000165

AC:

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

Dec 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 aspartic acid with asparagine at codon 1235 of the SMARCA4 protein (p.Asp1235Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs759192892, ExAC 0.006%). This variant has not been reported in the literature in individuals with SMARCA4-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Nov 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D1235N variant (also known as c.3703G>A), located in coding exon 25 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 3703. The aspartic acid at codon 1235 is replaced by asparagine, 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. 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). 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

0.92

BayesDel_addAF

Benign

-0.00057

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.67

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.17

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

PhyloP100

9.6

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.0

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

REVEL

Uncertain

0.51

Sift

Uncertain

0.024

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

Sift4G

Uncertain

0.024

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

Polyphen

0.068

B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.

Vest4

0.80

MutPred

0.58

Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);Loss of ubiquitination at K1237 (P = 0.0272);.;Loss of ubiquitination at K1237 (P = 0.0272);.;.;.;

MVP

0.92

MPC

1.5

ClinPred

0.92

GERP RS

4.7

PromoterAI

0.0016

Neutral

(source)

Varity_R

0.41

gMVP

0.94

Mutation Taster

=61/39

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

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