rs767743765

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 4P and 7B. PM1PM2BP4_ModerateBP6BS1

The NM_001387283.1(SMARCA4):c.2455G>A(p.Ala819Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,716 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A819V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.74

Publications

0 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 -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001387283.1

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24818218).

BP6

Variant 19-11018973-G-A is Benign according to our data. Variant chr19-11018973-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 484839.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000342 (5/1461716) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.0000609. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMARCA4	ENST00000646693.2 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 18 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 17 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5 link	c.2455G>A	p.Ala819Thr	missense_variant	Exon 18 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1 link	c.1867G>A	p.Ala623Thr	missense_variant	Exon 14 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1 link	c.1099G>A	p.Ala367Thr	missense_variant	Exon 10 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1 link	c.1180G>A	p.Ala394Thr	missense_variant	Exon 10 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1 link	c.940G>A	p.Ala314Thr	missense_variant	Exon 9 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1 link	c.808G>A	p.Ala270Thr	missense_variant	Exon 8 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111852

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Sep 08, 2024

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 819 of the SMARCA4 protein (p.Ala819Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 484839). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome

Benign:1

Apr 24, 2023

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

0.090

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Benign

0.42

DEOGEN2

Uncertain

0.53

D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

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

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.25

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

MetaSVM

Uncertain

0.046

MutationAssessor

Benign

0.84

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.

PhyloP100

1.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.15

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

REVEL

Uncertain

0.34

Sift

Benign

0.74

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

Sift4G

Benign

0.70

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

Polyphen

0.0020

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

Vest4

0.23

MutPred

0.38

Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);Loss of stability (P = 0.1653);.;Loss of stability (P = 0.1653);.;.;.;.;

MVP

0.78

MPC

1.8

ClinPred

0.17

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.25

gMVP

0.78

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over