chr19-10987920-T-C

Position:

chr19-10987920-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001387283.1(SMARCA4):c.1114T>C(p.Tyr372His) variant causes a missense change. The variant allele was found at a frequency of 0.0139 in 1,612,450 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 206 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 6.14

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 -19 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=0.008926064).

BP6

Variant 19-10987920-T-C is Benign according to our data. Variant chr19-10987920-T-C is described in ClinVar as [Benign]. Clinvar id is 126355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10987920-T-C is described in Lovd as [Benign]. Variant chr19-10987920-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0101 (1541/152168) while in subpopulation AMR AF= 0.0153 (233/15272). AF 95% confidence interval is 0.0144. There are 11 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1541 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.1114T>C	p.Tyr372His	missense_variant	6/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.1114T>C	p.Tyr372His	missense_variant	6/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.1114T>C	p.Tyr372His	missense_variant	6/36		NM_001387283.1	ENSP00000495368
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.1114T>C	p.Tyr372His	missense_variant	6/35	1	NM_003072.5	ENSP00000343896	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1541

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00329

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00961

AC:

2310

AN:

240404

Hom.:

AF XY:

0.00950

AC XY:

1247

AN XY:

131202

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00223

Gnomad FIN exome

AF:

0.00446

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0143

AC:

20822

AN:

1460282

Hom.:

206

Cov.:

AF XY:

0.0140

AC XY:

10145

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00261

Gnomad4 FIN exome

AF:

0.00498

Gnomad4 NFE exome

AF:

0.0169

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152168

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

706

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00328

Gnomad4 AMR

AF:

0.0153

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00565

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0121

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00278

AC:

ESP6500EA

AF:

0.0152

AC:

127

ExAC

AF:

0.00953

AC:

1153

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal dominant 16

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2015

This alteration is classified as 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

0.58

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.20

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

Eigen

Benign

-0.12

Eigen_PC

Benign

0.039

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0089

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

MetaSVM

Benign

-0.46

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

0.88

PROVEAN

Benign

-0.20

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

REVEL

Uncertain

0.45

Sift

Benign

0.49

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

Sift4G

Benign

0.53

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

Polyphen

0.040

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

Vest4

0.52

MVP

0.91

MPC

1.7

ClinPred

0.0091

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.84

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