X-129471263-C-T

Position:

• chrX-129471263-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001282874.2(SMARCA1):​c.2506G>A​(p.Asp836Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.2506G>A	p.Asp836Asn	missense_variant	20/25	ENST00000371121.5	NP_001269803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA1	ENST00000371121.5	c.2506G>A	p.Asp836Asn	missense_variant	20/25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.2470G>A	p.Asp824Asn	missense_variant	19/24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.2506G>A	p.Asp836Asn	missense_variant	20/25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.2824G>A		non_coding_transcript_exon_variant	18/23	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087662 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 353520

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.2506G>A (p.D836N) alteration is located in exon 20 (coding exon 20) of the SMARCA1 gene. This alteration results from a G to A substitution at nucleotide position 2506, causing the aspartic acid (D) at amino acid position 836 to be replaced by an asparagine (N). 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	Benign	0.23
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.63	P;.;P
Vest4		0.61
MutPred		0.49		Gain of methylation at K833 (P = 0.0645);.;Gain of methylation at K833 (P = 0.0645);
MVP		0.92
MPC		0.86
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.68

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: rs1933109246; hg19: chrX-128605240; COSMIC: COSV64410674;