chrX-129471259-C-G

Variant names:

• chrX-129471259-C-G
• rs34182579
• NM_001282874.2:c.2510G>C

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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
• Publications: 3 publications found

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, STRONG Submitted by: PanelApp Australia, Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282874.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	NM_001282874.2	MANE Select	c.2510G>C	p.Gly837Ala	missense	Exon 20 of 25	NP_001269803.1	B7ZLQ5
	SMARCA1	NM_001282875.2		c.2474G>C	p.Gly825Ala	missense	Exon 19 of 24	NP_001269804.1	A0A0A0MRP6
	SMARCA1	NM_003069.5		c.2510G>C	p.Gly837Ala	missense	Exon 20 of 25	NP_003060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	ENST00000371121.5	TSL:1 MANE Select	c.2510G>C	p.Gly837Ala	missense	Exon 20 of 25	ENSP00000360162.4	B7ZLQ5
	SMARCA1	ENST00000371123.5	TSL:1	c.2474G>C	p.Gly825Ala	missense	Exon 19 of 24	ENSP00000360164.2	A0A0A0MRP6
	SMARCA1	ENST00000371122.8	TSL:1	c.2510G>C	p.Gly837Ala	missense	Exon 20 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 917 AN: 111808 Hom.: 14 Cov.: 23

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

GnomAD2 exomes AF: 0.00242 AC: 437 AN: 180376 AF XY: 0.00135

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 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

African (AFR) AF: 0.0306 AC: 798 AN: 26120

American (AMR) AF: 0.00180 AC: 63 AN: 35063

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19279

East Asian (EAS) AF: 0.00 AC: 0 AN: 30055

South Asian (SAS) AF: 0.000168 AC: 9 AN: 53413

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00538 AC: 22 AN: 4091

European-Non Finnish (NFE) AF: 0.0000325 AC: 27 AN: 831103

Other (OTH) AF: 0.00223 AC: 102 AN: 45651

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

African (AFR) AF: 0.0284 AC: 874 AN: 30828

American (AMR) AF: 0.00228 AC: 24 AN: 10540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.000379 AC: 1 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6046

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53183

Other (OTH) AF: 0.00791 AC: 12 AN: 1518

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.90	N
PhyloP100		3.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.15	N
REVEL	Uncertain	0.30
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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