chrX-129471242-G-C

Variant names:

• chrX-129471242-G-C
• rs1407269659
• NM_001282874.2:c.2527C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001282874.2(SMARCA1):​c.2527C>G​(p.Pro843Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000736 in 1,086,246 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000074 (0 hom. 3 hem.)
• Consequence: SMARCA1 NM_001282874.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.337
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032043308).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.2527C>G	p.Pro843Ala	missense	Exon 20 of 25	NP_001269803.1	B7ZLQ5
	SMARCA1	NM_001282875.2		c.2491C>G	p.Pro831Ala	missense	Exon 19 of 24	NP_001269804.1	A0A0A0MRP6
	SMARCA1	NM_003069.5		c.2527C>G	p.Pro843Ala	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.2527C>G	p.Pro843Ala	missense	Exon 20 of 25	ENSP00000360162.4	B7ZLQ5
	SMARCA1	ENST00000371123.5	TSL:1	c.2491C>G	p.Pro831Ala	missense	Exon 19 of 24	ENSP00000360164.2	A0A0A0MRP6
	SMARCA1	ENST00000371122.8	TSL:1	c.2527C>G	p.Pro843Ala	missense	Exon 20 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000336 AC: 6 AN: 178762 AF XY: 0.0000472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000446

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000736 AC: 8 AN: 1086246 Hom.: 0 Cov.: 26 AF XY: 0.00000851 AC XY: 3 AN XY: 352380

African (AFR) AF: 0.00 AC: 0 AN: 26094

American (AMR) AF: 0.00 AC: 0 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19248

East Asian (EAS) AF: 0.000267 AC: 8 AN: 30011

South Asian (SAS) AF: 0.00 AC: 0 AN: 53112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832706

Other (OTH) AF: 0.00 AC: 0 AN: 45668

GnomAD4 genome Cov.: 23

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	0.042
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.6
DANN	Benign	0.70
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.34
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.22
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.32		Loss of glycosylation at P843 (P = 0.044)
MVP		0.62
MPC		0.59
ClinPred		0.028	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.26
Mutation Taster		=100/0	polymorphism

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: rs1407269659; hg19: chrX-128605219;