rs148530368

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001387283.1(SMARCA4):c.1076G>A(p.Arg359Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,612,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R359W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 1.61

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 -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.029369116).

BP6

Variant 19-10987882-G-A is Benign according to our data. Variant chr19-10987882-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000377 (551/1460698) while in subpopulation NFE AF= 0.000463 (515/1111896). AF 95% confidence interval is 0.00043. There are 0 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	6/36	ENST00000646693.2
SMARCA4	NM_003072.5 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	6/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	6/36		NM_001387283.1
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.1076G>A	p.Arg359Gln	missense_variant	6/35	1	NM_003072.5	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000187

AC:

AN:

241264

Hom.:

AF XY:

0.000175

AC XY:

AN XY:

131646

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000339

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000377

AC:

551

AN:

1460698

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

256

AN XY:

726620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.000463

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000210

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000220

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.000463

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including acute lymphoblastic leukemia (ALL) and other cancers (Zhang 2015, Wang 2017); This variant is associated with the following publications: (PMID: 26580448, 26353884, 23718828, 27363283) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SMARCA4: PP2, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2018	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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Coffin-Siris syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

SMARCA4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.16

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

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.64

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

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.029

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

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.73

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

MutationTaster

Benign

0.70

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

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.53

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

REVEL

Benign

0.23

Sift

Benign

0.66

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

Sift4G

Benign

0.63

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

Polyphen

0.0040

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

Vest4

0.30

MVP

0.43

MPC

1.4

ClinPred

0.022

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.12

gMVP

0.55

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