X-129465870-T-C

Variant names:

• chrX-129465870-T-C
• NM_001282874.2:c.2791A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001282874.2(SMARCA1):​c.2791A>G​(p.Ser931Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000943 in 1,060,517 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.2791A>G	p.Ser931Gly	missense_variant	Exon 22 of 25	ENST00000371121.5	NP_001269803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA1	ENST00000371121.5	c.2791A>G	p.Ser931Gly	missense_variant	Exon 22 of 25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.2755A>G	p.Ser919Gly	missense_variant	Exon 21 of 24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.2791A>G	p.Ser931Gly	missense_variant	Exon 22 of 25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.3109A>G		non_coding_transcript_exon_variant	Exon 20 of 23	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.43e-7 AC: 1 AN: 1060517 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 333143

Gnomad4 AFR exome AF: 0.0000395

Gnomad4 AMR exome AF: 0.00

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 Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	0.020	D
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.44	T;T;.
Sift4G	Benign	0.37	T;T;T
Polyphen		0.017	B;.;B
Vest4		0.56
MutPred		0.41		Loss of phosphorylation at S931 (P = 0.0062);.;Loss of phosphorylation at S931 (P = 0.0062);
MVP		0.99
MPC		0.57
ClinPred		0.72	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-128599847;