rs769096295

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001387283.1(SMARCA4):c.679G>A(p.Ala227Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000777 in 1,545,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A227S) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.65

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16652921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 5 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 4 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.679G>A	p.Ala227Thr	missense_variant	Exon 5 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

141392

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000790

AC:

AN:

1392998

Hom.:

Cov.:

AF XY:

0.00000582

AC XY:

AN XY:

687416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31604

American (AMR)

AF:

0.00

AC:

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25112

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1078960

Other (OTH)

AF:

0.0000173

AC:

AN:

57964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Uncertain:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Rhabdoid tumor predisposition syndrome 2

Uncertain:2

Aug 21, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 227 of the SMARCA4 protein (p.Ala227Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SMARCA4-related conditions (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 408603). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided

Uncertain:1

Nov 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.0000066 (1/152210 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been identified in an individual with advanced cancer (PMID: 28873162 (2017)). 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.

Hereditary cancer-predisposing syndrome

Benign:1

Sep 02, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.073

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

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

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.0

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

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

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

PhyloP100

2.7

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.18

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

REVEL

Benign

0.17

Sift

Benign

0.18

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

Sift4G

Benign

0.57

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

Vest4

0.28

ClinPred

0.25

GERP RS

5.0

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.027

gMVP

0.072

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over