rs758091260

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001387283.1(SMARCA4):c.952G>A(p.Val318Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000469 in 1,598,486 control chromosomes in the GnomAD database, including 1 homozygotes. 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. V318A) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 8.02

Publications

2 publications found

Variant links:

COSMIC-nc: COSV60812370

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21264735).

BP6

Variant 19-10987758-G-A is Benign according to our data. Variant chr19-10987758-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408669.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000498 (72/1446842) while in subpopulation SAS AF = 0.000412 (35/84878). AF 95% confidence interval is 0.000305. There are 1 homozygotes in GnomAdExome4. There are 47 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387283.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA4	NM_001387283.1	MANE Plus Clinical	c.952G>A	p.Val318Ile	missense	Exon 6 of 36	NP_001374212.1
SMARCA4	NM_003072.5	MANE Select	c.952G>A	p.Val318Ile	missense	Exon 6 of 35	NP_003063.2
SMARCA4	NM_001128849.3		c.952G>A	p.Val318Ile	missense	Exon 6 of 36	NP_001122321.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA4	ENST00000646693.2	MANE Plus Clinical	c.952G>A	p.Val318Ile	missense	Exon 6 of 36	ENSP00000495368.1
SMARCA4	ENST00000344626.10	TSL:1 MANE Select	c.952G>A	p.Val318Ile	missense	Exon 6 of 35	ENSP00000343896.4
SMARCA4	ENST00000643549.1		c.952G>A	p.Val318Ile	missense	Exon 6 of 35	ENSP00000493975.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151644

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:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

212686

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000926

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000666

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000498

AC:

AN:

1446842

Hom.:

Cov.:

AF XY:

0.0000654

AC XY:

AN XY:

718576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33088

American (AMR)

AF:

0.0000922

AC:

AN:

43402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25722

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38936

South Asian (SAS)

AF:

0.000412

AC:

AN:

84878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.0000271

AC:

AN:

1105014

Other (OTH)

AF:

0.0000335

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000198

AC:

AN:

151644

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41222

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000209

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67874

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000227

ExAC

AF:

0.000135

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Intellectual disability, autosomal dominant 16 (1)

not provided (1)

Rhabdoid tumor predisposition syndrome 2 (1)

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.061

MutationAssessor

Benign

1.8

PhyloP100

8.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.28

REVEL

Uncertain

0.41

Sift

Benign

0.18

Sift4G

Benign

0.26

Polyphen

0.91

Vest4

0.45

MutPred

0.18

Gain of catalytic residue at P320 (P = 0.0557)

MVP

0.68

MPC

0.35

ClinPred

0.16

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.061

gMVP

0.035

Mutation Taster

=100/0

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over