X-129471259-C-G

Position:

• chrX-129471259-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001282874.2(SMARCA1):​c.2510G>C​(p.Gly837Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,197,113 control chromosomes in the GnomAD database, including 27 homozygotes. There are 492 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., 250 hem., cov: 23)
  • Exomes 𝑓: 0.00094 (13 hom. 242 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025115997).
• BP6: Variant X-129471259-C-G is Benign according to our data. Variant chrX-129471259-C-G is described in ClinVar as [Benign]. Clinvar id is 710616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00823 (921/111862) while in subpopulation AFR AF= 0.0284 (874/30828). AF 95% confidence interval is 0.0268. There are 14 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA1	NM_001282874.2	c.2510G>C	p.Gly837Ala	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.2510G>C	p.Gly837Ala	missense_variant	20/25	1	NM_001282874.2	ENSP00000360162.4
SMARCA1	ENST00000371123.5	c.2474G>C	p.Gly825Ala	missense_variant	19/24	1		ENSP00000360164.2
SMARCA1	ENST00000371122.8	c.2510G>C	p.Gly837Ala	missense_variant	20/25	1		ENSP00000360163.4
SMARCA1	ENST00000617310.4	n.2828G>C		non_coding_transcript_exon_variant	18/23	2

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 917 AN: 111808 Hom.: 14 Cov.: 23 AF XY: 0.00729 AC XY: 248 AN XY: 34028

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00228

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00801

GnomAD3 exomes AF: 0.00242 AC: 437 AN: 180376 Hom.: 7 AF XY: 0.00135 AC XY: 88 AN XY: 65052

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000941 AC: 1021 AN: 1085251 Hom.: 13 Cov.: 25 AF XY: 0.000689 AC XY: 242 AN XY: 351197

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.00823 AC: 921 AN: 111862 Hom.: 14 Cov.: 23 AF XY: 0.00733 AC XY: 250 AN XY: 34092

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00228

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.00791

Alfa AF: 0.000566 Hom.: 14

Bravo AF: 0.00933

ESP6500AA AF: 0.0276 AC: 106

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.00273 AC: 331

EpiCase AF: 0.000387

EpiControl AF: 0.000241

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0089	T;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.90	N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.15	N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.16	T;T;.
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.15
MVP		0.69
MPC		0.66
ClinPred		0.018	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.14
gMVP		0.34

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: rs34182579; hg19: chrX-128605236; COSMIC: COSV100946592;