Variant chrX-129481149-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001282874.2(SMARCA1):c.2254G>A(p.Glu752Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,204,170 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

SMARCA1
NM_001282874.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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 links:

SMARCA1 (HGNC:):

SMARCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA1	NM_001282874.2 linkuse as main transcript	c.2254G>A	p.Glu752Lys	missense_variant	18/25	ENST00000371121.5	NP_001269803.1	B7ZLQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMARCA1	ENST00000371121.5 linkuse as main transcript	c.2254G>A	p.Glu752Lys	missense_variant	18/25	1	NM_001282874.2	ENSP00000360162.4	B7ZLQ5
SMARCA1	ENST00000371123.5 linkuse as main transcript	c.2218G>A	p.Glu740Lys	missense_variant	17/24	1		ENSP00000360164.2	A0A0A0MRP6
SMARCA1	ENST00000371122.8 linkuse as main transcript	c.2254G>A	p.Glu752Lys	missense_variant	18/25	1		ENSP00000360163.4	P28370-1
SMARCA1	ENST00000617310.4 linkuse as main transcript	n.2312G>A		non_coding_transcript_exon_variant	17/23	2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34170

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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

GnomAD4 exome

AF:

9.16e-7

AC:

AN:

1092170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000286

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34170

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

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

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2024

The c.2254G>A (p.E752K) alteration is located in exon 18 (coding exon 18) of the SMARCA1 gene. This alteration results from a G to A substitution at nucleotide position 2254, causing the glutamic acid (E) at amino acid position 752 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.012

D;D;.

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.97

D;.;D

Vest4

0.76

MutPred

0.40

Gain of MoRF binding (P = 0.0046);.;Gain of MoRF binding (P = 0.0046);

MVP

0.99

MPC

1.5

ClinPred

0.99

GERP RS

5.8

Varity_R

0.91

gMVP

0.79

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