rs768899897

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001387283.1(SMARCA4):c.4840G>A(p.Glu1614Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,848 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E1614D) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.27

Publications

6 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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24684909).

BP6

Variant 19-11059861-G-A is Benign according to our data. Variant chr19-11059861-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408629.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4840G>A	p.Glu1614Lys	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4744G>A	p.Glu1582Lys	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.4840G>A	p.Glu1614Lys	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.4744G>A	p.Glu1582Lys	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.4750G>A	p.Glu1584Lys	missense_variant	Exon 33 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 33 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 32 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.4654G>A	p.Glu1552Lys	missense_variant	Exon 32 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.4651G>A	p.Glu1551Lys	missense_variant	Exon 33 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.4165G>A	p.Glu1389Lys	missense_variant	Exon 30 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.3394G>A	p.Glu1132Lys	missense_variant	Exon 26 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.3376G>A	p.Glu1126Lys	missense_variant	Exon 25 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.3238G>A	p.Glu1080Lys	missense_variant	Exon 25 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.3004G>A	p.Glu1002Lys	missense_variant	Exon 23 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4 link	c.808G>A	p.Glu270Lys	missense_variant	Exon 6 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248502

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111938

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1614 of the SMARCA4 protein (p.Glu1614Lys). This variant is present in population databases (rs768899897, gnomAD 0.006%). 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: 408629). 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 not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

not provided

Uncertain:1

Apr 05, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 04, 2022

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

Benign

0.25

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

0.015

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.25

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

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.4

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

PhyloP100

4.3

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.69

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

REVEL

Uncertain

0.40

Sift

Benign

0.23

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

Sift4G

Benign

0.52

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

Polyphen

0.45

P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.

Vest4

0.44

MutPred

0.17

.;.;Gain of ubiquitination at E1614 (P = 0.0128);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of ubiquitination at E1614 (P = 0.0128);.;.;.;.;

MVP

0.74

MPC

1.1

ClinPred

0.29

GERP RS

3.3

Varity_R

0.19

gMVP

0.67

Mutation Taster

=78/22

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