19-10987757-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001387283.1(SMARCA4):c.951C>T(p.Ala317=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,600,240 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A317A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -6.38

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-10987757-C-T is Benign according to our data. Variant chr19-10987757-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000921 (14/152090) while in subpopulation AMR AF= 0.000524 (8/15258). AF 95% confidence interval is 0.000261. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.951C>T	p.Ala317=	synonymous_variant	6/36	ENST00000646693.2
SMARCA4	NM_003072.5 linkuse as main transcript	c.951C>T	p.Ala317=	synonymous_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.951C>T	p.Ala317=	synonymous_variant	6/36		NM_001387283.1
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.951C>T	p.Ala317=	synonymous_variant	6/35	1	NM_003072.5	P4	P51532-1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000751

AC:

AN:

213142

Hom.:

AF XY:

0.0000850

AC XY:

AN XY:

117606

show subpopulations

Gnomad AFR exome

AF:

0.0000838

Gnomad AMR exome

AF:

0.000277

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000122

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000106

Gnomad NFE exome

AF:

0.0000221

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000863

AC:

125

AN:

1448150

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

719344

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000276

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000593

Gnomad4 NFE exome

AF:

0.0000931

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000102

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SMARCA4: BP4, BP7 -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2015	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 29, 2021	- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

SMARCA4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

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

BayesDel_noAF

Benign

-0.87

Cadd

Benign

0.25

Dann

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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