Genetic Variant SMARCA1:p.Arg981Lys (chrX-129465608-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001282874.2(SMARCA1):c.2942G>A(p.Arg981Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000275 in 1,198,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000024 ( 0 hom. 3 hem. )

Consequence

SMARCA1
NM_001282874.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

Publications

0 publications found

Variant links:

Genes affected

SMARCA1 (HGNC:11097): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1) This gene encodes a member of the SWI/SNF family of proteins. The encoded protein is an ATPase which is expressed in diverse tissues and contributes to the chromatin remodeling complex that is involved in transcription. The protein may also play a role in DNA damage, growth inhibition and apoptosis of cancer cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

SMARCA1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics
X-linked intellectual disability
Inheritance: XL Classification: LIMITED Submitted by: ClinGen
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SMARCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051436514).

BS2

High Hemizygotes in GnomAd4 at 2 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282874.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA1	NM_001282874.2	MANE Select	c.2942G>A	p.Arg981Lys	missense	Exon 23 of 25	NP_001269803.1	B7ZLQ5
SMARCA1	NM_001282875.2		c.2906G>A	p.Arg969Lys	missense	Exon 22 of 24	NP_001269804.1	A0A0A0MRP6
SMARCA1	NM_003069.5		c.2942G>A	p.Arg981Lys	missense	Exon 23 of 25	NP_003060.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA1	ENST00000371121.5	TSL:1 MANE Select	c.2942G>A	p.Arg981Lys	missense	Exon 23 of 25	ENSP00000360162.4	B7ZLQ5
SMARCA1	ENST00000371123.5	TSL:1	c.2906G>A	p.Arg969Lys	missense	Exon 22 of 24	ENSP00000360164.2	A0A0A0MRP6
SMARCA1	ENST00000371122.8	TSL:1	c.2942G>A	p.Arg981Lys	missense	Exon 23 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes

AF:

0.0000625

AC:

AN:

111995

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000569

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:

0.000660

GnomAD2 exomes

AF:

0.0000386

AC:

AN:

181388

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000259

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:

0.0000239

AC:

AN:

1086624

Hom.:

Cov.:

AF XY:

0.00000852

AC XY:

AN XY:

352294

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26184

American (AMR)

AF:

0.000399

AC:

AN:

35108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19305

East Asian (EAS)

AF:

0.00

AC:

AN:

30116

South Asian (SAS)

AF:

0.00

AC:

AN:

53625

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4081

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

831978

Other (OTH)

AF:

0.000241

AC:

AN:

45714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000625

AC:

AN:

112051

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34233

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30922

American (AMR)

AF:

0.000568

AC:

AN:

10555

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3589

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53157

Other (OTH)

AF:

0.000651

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000102

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.017

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.58

MutationAssessor

Benign

-0.28

PhyloP100

5.1

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.71

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.17

MVP

0.85

MPC

0.62

ClinPred

0.098

GERP RS

4.7

Varity_R

0.15

gMVP

0.54

Mutation Taster

=84/16

polymorphism

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over