rs761515593

chr19-10986548-G-Achr19-10986548-G-Cchr19-10986548-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001387283.1(SMARCA4):c.715G>A(p.Gly239Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000286 in 1,539,492 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. G239C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.59

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant where missense usually causes diseases, SMARCA4

BP4

Computational evidence support a benign effect (MetaRNN=0.19692013).

BP6

Variant 19-10986548-G-A is Benign according to our data. Variant chr19-10986548-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000031 (43/1387604) while in subpopulation SAS AF= 0.000379 (30/79166). AF 95% confidence interval is 0.000272. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.715G>A	p.Gly239Ser	missense_variant	4/36	ENST00000646693.2
SMARCA4	NM_003072.5 linkuse as main transcript	c.715G>A	p.Gly239Ser	missense_variant	4/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.715G>A	p.Gly239Ser	missense_variant	4/36		NM_001387283.1
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.715G>A	p.Gly239Ser	missense_variant	4/35	1	NM_003072.5	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151888

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000668

AC:

AN:

134742

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

73636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000356

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1387604

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

684870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000648

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 17, 2022

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00036 (8/22456 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

SMARCA4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

The SMARCA4 c.715G>A variant is predicted to result in the amino acid substitution p.Gly239Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11097224-G-A), which is likely too common for an undocumented disease-causing variant. In ClinVar, this variant is interpreted as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/238514/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Intellectual disability, autosomal dominant 16

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2019

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

0.081

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

Cadd

Uncertain

Dann

Benign

0.93

DEOGEN2

Benign

0.20

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

Eigen

Benign

0.066

Eigen_PC

Benign

-0.0083

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

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

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.36

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

REVEL

Uncertain

0.41

Sift

Benign

0.27

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

Sift4G

Benign

0.39

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

Polyphen

1.0

D;.;P;.;.;.;.;.;.;.;D;.;.;.;.;.;.;P

Vest4

0.51

MutPred

0.30

Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);Gain of phosphorylation at G239 (P = 9e-04);

MVP

0.81

MPC

0.39

ClinPred

0.14

GERP RS

4.5

Varity_R

0.092

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over