Genetic Variant SMARCA1:p.Thr858Ala (chrX-129468899-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001282874.2(SMARCA1):c.2572A>G(p.Thr858Ala) 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 benign 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: 7.86

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35408884).

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.2572A>G	p.Thr858Ala	missense	Exon 21 of 25	NP_001269803.1	B7ZLQ5
SMARCA1	NM_001282875.2		c.2536A>G	p.Thr846Ala	missense	Exon 20 of 24	NP_001269804.1	A0A0A0MRP6
SMARCA1	NM_003069.5		c.2572A>G	p.Thr858Ala	missense	Exon 21 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.2572A>G	p.Thr858Ala	missense	Exon 21 of 25	ENSP00000360162.4	B7ZLQ5
SMARCA1	ENST00000371123.5	TSL:1	c.2536A>G	p.Thr846Ala	missense	Exon 20 of 24	ENSP00000360164.2	A0A0A0MRP6
SMARCA1	ENST00000371122.8	TSL:1	c.2572A>G	p.Thr858Ala	missense	Exon 21 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1065715

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

334403

African (AFR)

AF:

0.00

AC:

AN:

25629

American (AMR)

AF:

0.00

AC:

AN:

33182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18698

East Asian (EAS)

AF:

0.00

AC:

AN:

29810

South Asian (SAS)

AF:

0.00

AC:

AN:

50140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40277

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4041

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

818986

Other (OTH)

AF:

0.00

AC:

AN:

44952

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.062

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.35

MetaSVM

Uncertain

-0.011

MutationAssessor

Benign

1.6

PhyloP100

7.9

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.55

Sift

Benign

0.36

Sift4G

Benign

0.95

Polyphen

0.095

Vest4

0.48

MutPred

0.23

Loss of phosphorylation at T854 (P = 0.096)

MVP

0.98

MPC

0.63

ClinPred

0.48

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.58

Mutation Taster

=46/54

disease causing

(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