chrX-129471280-T-C

Variant names:

• chrX-129471280-T-C
• rs780004002
• NM_001282874.2:c.2489A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001282874.2(SMARCA1):​c.2489A>G​(p.Glu830Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,085,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.2489A>G	p.Glu830Gly	missense	Exon 20 of 25	NP_001269803.1	B7ZLQ5
	SMARCA1	NM_001282875.2		c.2453A>G	p.Glu818Gly	missense	Exon 19 of 24	NP_001269804.1	A0A0A0MRP6
	SMARCA1	NM_003069.5		c.2489A>G	p.Glu830Gly	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.2489A>G	p.Glu830Gly	missense	Exon 20 of 25	ENSP00000360162.4	B7ZLQ5
	SMARCA1	ENST00000371123.5	TSL:1	c.2453A>G	p.Glu818Gly	missense	Exon 19 of 24	ENSP00000360164.2	A0A0A0MRP6
	SMARCA1	ENST00000371122.8	TSL:1	c.2489A>G	p.Glu830Gly	missense	Exon 20 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180373 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085576 Hom.: 0 Cov.: 26 AF XY: 0.00000284 AC XY: 1 AN XY: 351788

African (AFR) AF: 0.00 AC: 0 AN: 26130

American (AMR) AF: 0.00 AC: 0 AN: 35084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30089

South Asian (SAS) AF: 0.00 AC: 0 AN: 53500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40473

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 831272

Other (OTH) AF: 0.00 AC: 0 AN: 45660

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.028	D
Polyphen		0.88	P
Vest4		0.45
MutPred		0.52		Loss of stability (P = 0.0378)
MVP		0.93
MPC		1.3
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.70
Mutation Taster		=27/73	disease causing

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: rs780004002; hg19: chrX-128605257;