rs1060499736

Variant names:

• chrX-129523364-G-A
• rs1060499736
• NM_001282874.2:c.7C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001282874.2(SMARCA1):​c.7C>T​(p.Gln3*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA1 NM_001282874.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.73
• Publications: 2 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 Submitted by: 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-129523364-G-A is Pathogenic according to our data. Variant chrX-129523364-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402137.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	NM_001282874.2	MANE Select	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 25	NP_001269803.1
	SMARCA1	NM_001282875.2		c.7C>T	p.Gln3*	stop_gained	Exon 1 of 24	NP_001269804.1
	SMARCA1	NM_003069.5		c.7C>T	p.Gln3*	stop_gained	Exon 1 of 25	NP_003060.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA1	ENST00000371121.5	TSL:1 MANE Select	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 25	ENSP00000360162.4
	SMARCA1	ENST00000371123.5	TSL:1	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 24	ENSP00000360164.2
	SMARCA1	ENST00000371122.8	TSL:1	c.7C>T	p.Gln3*	stop_gained	Exon 1 of 25	ENSP00000360163.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1053704 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 333930

African (AFR) AF: 0.00 AC: 0 AN: 24925

American (AMR) AF: 0.00 AC: 0 AN: 30712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17358

East Asian (EAS) AF: 0.00 AC: 0 AN: 28982

South Asian (SAS) AF: 0.00 AC: 0 AN: 49167

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 822257

Other (OTH) AF: 0.00 AC: 0 AN: 44277

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.48	N
PhyloP100		1.7
Vest4		0.67
GERP RS		3.1
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=29/171	disease causing (ClinVar)

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: rs1060499736; hg19: chrX-128657341;