Genetic Variant SMARCA1:p.Ile1023Thr (chrX-129448406-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001282874.2(SMARCA1):c.3068T>C(p.Ile1023Thr) 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: 22)

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: 8.27

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 Submitted by: 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 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 rank	MANE	Protein	UniProt
SMARCA1	NM_001282874.2 link	c.3068T>C	p.Ile1023Thr	missense_variant	Exon 24 of 25	ENST00000371121.5	NP_001269803.1	B7ZLQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA1	ENST00000371121.5 link	c.3068T>C	p.Ile1023Thr	missense_variant	Exon 24 of 25	1	NM_001282874.2	ENSP00000360162.4	B7ZLQ5
SMARCA1	ENST00000371123.5 link	c.3032T>C	p.Ile1011Thr	missense_variant	Exon 23 of 24	1		ENSP00000360164.2	A0A0A0MRP6
SMARCA1	ENST00000371122.8 link	c.3068T>C	p.Ile1023Thr	missense_variant	Exon 24 of 25	1		ENSP00000360163.4	P28370-1
SMARCA1	ENST00000617310.4 link	n.3386T>C		non_coding_transcript_exon_variant	Exon 22 of 23	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1083598

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

350106

African (AFR)

AF:

0.00

AC:

AN:

26103

American (AMR)

AF:

0.00

AC:

AN:

34964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19256

East Asian (EAS)

AF:

0.00

AC:

AN:

30051

South Asian (SAS)

AF:

0.00

AC:

AN:

53334

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40303

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829901

Other (OTH)

AF:

0.00

AC:

AN:

45598

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked intellectual disability

Uncertain:1

Dec 21, 2022

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.64

BayesDel_noAF

Pathogenic

0.69

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;.;.

PhyloP100

8.3

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.4

D;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.83

MutPred

0.67

Gain of loop (P = 0.0013);.;Gain of loop (P = 0.0013);

MVP

1.0

MPC

1.4

ClinPred

1.0

GERP RS

5.9

Varity_R

0.84

gMVP

0.82

Mutation Taster

=51/49

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over