NM_001387283.1:c.4174A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001387283.1(SMARCA4):c.4174A>G(p.Ile1392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,594,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 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 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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=0.079690814).

BP6

Variant 19-11039461-A-G is Benign according to our data. Variant chr19-11039461-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212256.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000046 (7/152214) while in subpopulation AFR AF= 0.000169 (7/41448). AF 95% confidence interval is 0.0000789. 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 rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.4174A>G	p.Ile1392Val	missense_variant	Exon 30 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.4171-1846A>G		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.4174A>G	p.Ile1392Val	missense_variant	Exon 30 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000643549.1 link	c.4075A>G	p.Ile1359Val	missense_variant	Exon 29 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000344626.10 link	c.4171-1846A>G		intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000541122.6 link	c.4072-1837A>G		intron_variant	Intron 29 of 34	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.4072-1837A>G		intron_variant	Intron 28 of 33			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.4072-1837A>G		intron_variant	Intron 28 of 33			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.4072-1837A>G		intron_variant	Intron 29 of 34	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.3583-1837A>G		intron_variant	Intron 26 of 31			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.2815-1837A>G		intron_variant	Intron 22 of 27			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.2797-1837A>G		intron_variant	Intron 21 of 26			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.2656-1837A>G		intron_variant	Intron 21 of 26			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.2524-1837A>G		intron_variant	Intron 20 of 24			ENSP00000494159.1	A0A2R8Y526
SMARCA4	ENST00000538456.4 link	c.328-1837A>G		intron_variant	Intron 3 of 7	3		ENSP00000495197.1	A0A2R8YFK5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000889

AC:

AN:

225050

Hom.:

AF XY:

0.00000810

AC XY:

AN XY:

123450

show subpopulations

Gnomad AFR exome

AF:

0.0000729

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000624

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:

0.0000118

AC:

AN:

1442340

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

716996

show subpopulations

Gnomad4 AFR exome

AF:

0.000124

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000209

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000837

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000319

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMARCA4 c.4174A>G (p.Ile1392Val) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.00022 (5/22426 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -

Jul 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 07, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 19, 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. -

not specified

Uncertain:1

May 09, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.17

DEOGEN2

Benign

0.0037

.;T;.;.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.46

T;.;.;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.080

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.44

Sift4G

Benign

1.0

.;.;.;.;T

Polyphen

0.022

.;B;.;.;B

Vest4

0.11

MVP

0.17

ClinPred

0.10

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