rs775807962

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001387283.1(SMARCA4):c.4256G>A(p.Arg1419His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,596,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.730

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 Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.13911858).

BP6

Variant 19-11039543-G-A is Benign according to our data. Variant chr19-11039543-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4256G>A	p.Arg1419His	missense_variant	Exon 30 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4171-1764G>A		intron_variant	Intron 29 of 34	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.4256G>A	p.Arg1419His	missense_variant	Exon 30 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000643549.1 link	c.4157G>A	p.Arg1386His	missense_variant	Exon 29 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000344626.10 link	c.4171-1764G>A		intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000541122.6 link	c.4072-1755G>A		intron_variant	Intron 29 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.4072-1755G>A		intron_variant	Intron 28 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.4072-1755G>A		intron_variant	Intron 28 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.4072-1755G>A		intron_variant	Intron 29 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.3583-1755G>A		intron_variant	Intron 26 of 31			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2815-1755G>A		intron_variant	Intron 22 of 27			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.2797-1755G>A		intron_variant	Intron 21 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.2656-1755G>A		intron_variant	Intron 21 of 26			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.2524-1755G>A		intron_variant	Intron 20 of 24			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 link	c.328-1755G>A		intron_variant	Intron 3 of 7	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000133

AC:

AN:

226320

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

123968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000609

Gnomad SAS 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:

0.00000554

AC:

AN:

1444706

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

718290

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000517

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Sep 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1419 of the SMARCA4 protein (p.Arg1419His). 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: 328037). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12

Uncertain:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Coffin-Siris syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 30, 2022

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

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T;.;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.75

T;.;.;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.59

PrimateAI

Uncertain

0.50

Sift4G

Uncertain

0.019

.;.;.;.;D

Polyphen

0.98

.;D;.;.;D

Vest4

0.19

MutPred

0.41

.;Loss of MoRF binding (P = 0.0078);.;.;Loss of MoRF binding (P = 0.0078);

MVP

0.19

ClinPred

0.16

GERP RS

-0.52

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