Genetic Variant SMARCA1:p.Asp836Asn (chrX-129471263-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001282874.2(SMARCA1):c.2506G>A(p.Asp836Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SMARCA1
NM_001282874.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

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.2506G>A	p.Asp836Asn	missense	Exon 20 of 25	NP_001269803.1	B7ZLQ5
SMARCA1	NM_001282875.2		c.2470G>A	p.Asp824Asn	missense	Exon 19 of 24	NP_001269804.1	A0A0A0MRP6
SMARCA1	NM_003069.5		c.2506G>A	p.Asp836Asn	missense	Exon 20 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.2506G>A	p.Asp836Asn	missense	Exon 20 of 25	ENSP00000360162.4	B7ZLQ5
SMARCA1	ENST00000371123.5	TSL:1	c.2470G>A	p.Asp824Asn	missense	Exon 19 of 24	ENSP00000360164.2	A0A0A0MRP6
SMARCA1	ENST00000371122.8	TSL:1	c.2506G>A	p.Asp836Asn	missense	Exon 20 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1087662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353520

African (AFR)

AF:

0.00

AC:

AN:

26172

American (AMR)

AF:

0.00

AC:

AN:

35093

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19294

East Asian (EAS)

AF:

0.00

AC:

AN:

30076

South Asian (SAS)

AF:

0.00

AC:

AN:

53534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

833175

Other (OTH)

AF:

0.00

AC:

AN:

45742

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

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

0.23

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.1

PhyloP100

7.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.54

Sift

Benign

0.13

Sift4G

Benign

0.14

Polyphen

0.63

Vest4

0.61

MutPred

0.49

Gain of methylation at K833 (P = 0.0645)

MVP

0.92

MPC

0.86

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.68

Mutation Taster

=61/39

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over