X-129465698-C-T

Variant names:

• chrX-129465698-C-T
• rs753758218
• NM_001282874.2:c.2852G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001282874.2(SMARCA1):​c.2852G>A​(p.Arg951His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,070,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000017 (0 hom. 5 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.2852G>A	p.Arg951His	missense_variant	Exon 23 of 25	ENST00000371121.5	NP_001269803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA1	ENST00000371121.5	c.2852G>A	p.Arg951His	missense_variant	Exon 23 of 25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.2816G>A	p.Arg939His	missense_variant	Exon 22 of 24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.2852G>A	p.Arg951His	missense_variant	Exon 23 of 25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.3170G>A		non_coding_transcript_exon_variant	Exon 21 of 23	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000168 AC: 18 AN: 1070090 Hom.: 0 Cov.: 27 AF XY: 0.0000146 AC XY: 5 AN XY: 341552

Gnomad4 AFR exome AF: 0.00

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: 0.0000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2852G>A (p.R951H) alteration is located in exon 23 (coding exon 23) of the SMARCA1 gene. This alteration results from a G to A substitution at nucleotide position 2852, causing the arginine (R) at amino acid position 951 to be replaced by a histidine (H). 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	0.74
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.053	T;T;.
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.38	B;.;B
Vest4		0.51
MutPred		0.61		Gain of helix (P = 0.0078);.;Gain of helix (P = 0.0078);
MVP		0.96
MPC		0.87
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.76

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

Other links and lift over

dbSNP: rs753758218; hg19: chrX-128599675; COSMIC: COSV64411701;