rs186823009

Positions:

Variant summary

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

The NM_001387283.1(SMARCA4):c.4187A>G(p.Asp1396Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000087 in 1,598,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.691

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:

SMARCA4 (HGNC:):

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=0.008718759).

BP6

Variant 19-11039474-A-G is Benign according to our data. Variant chr19-11039474-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 238453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000046 (7/152312) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 linkuse as main transcript	c.4187A>G	p.Asp1396Gly	missense_variant	30/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 linkuse as main transcript	c.4171-1833A>G		intron_variant		ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 linkuse as main transcript	c.4187A>G	p.Asp1396Gly	missense_variant	30/36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000643549.1 linkuse as main transcript	c.4088A>G	p.Asp1363Gly	missense_variant	29/35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000344626.10 linkuse as main transcript	c.4171-1833A>G		intron_variant		1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000541122.6 linkuse as main transcript	c.4072-1824A>G		intron_variant		5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 linkuse as main transcript	c.4072-1824A>G		intron_variant				ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 linkuse as main transcript	c.4072-1824A>G		intron_variant				ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 linkuse as main transcript	c.4072-1824A>G		intron_variant		5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 linkuse as main transcript	c.3583-1824A>G		intron_variant				ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 linkuse as main transcript	c.2815-1824A>G		intron_variant				ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 linkuse as main transcript	c.2797-1824A>G		intron_variant				ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 linkuse as main transcript	c.2656-1824A>G		intron_variant				ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 linkuse as main transcript	c.2524-1824A>G		intron_variant				ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 linkuse as main transcript	c.328-1824A>G		intron_variant		3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152194

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:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000249

AC:

AN:

229232

Hom.:

AF XY:

0.000318

AC XY:

AN XY:

125618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000362

GnomAD4 exome

AF:

0.0000913

AC:

132

AN:

1446156

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

719108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00150

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74480

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:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000341

AC:

Asia WGS

AF:

0.00115

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	Sep 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SMARCA4: PP2, BP4, BS1, BS2 -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2022	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 15, 2022	- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

SMARCA4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

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_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

.;T;.;.;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.0075

LIST_S2

Benign

0.68

T;.;.;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0087

T;T;T;T;T

MetaSVM

Benign

-0.47

PrimateAI

Benign

0.44

Sift4G

Uncertain

0.041

.;.;.;.;D

Polyphen

0.81

.;P;.;.;P

Vest4

0.16

MutPred

0.40

.;Gain of MoRF binding (P = 0.0269);.;.;Gain of MoRF binding (P = 0.0269);

MVP

0.15

ClinPred

0.048

GERP RS

0.73

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