chrX-129448402-CTCAA-C

Variant names:

• chrX-129448402-CTCAA-C
• NM_001282874.2:c.3068_3071delTTGA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001282874.2(SMARCA1):​c.3068_3071delTTGA​(p.Ile1023ArgfsTer45) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SMARCA1 NM_001282874.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.27
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.3068_3071delTTGA	p.Ile1023ArgfsTer45	frameshift	Exon 24 of 25	NP_001269803.1	B7ZLQ5
	SMARCA1	NM_001282875.2		c.3032_3035delTTGA	p.Ile1011ArgfsTer45	frameshift	Exon 23 of 24	NP_001269804.1	A0A0A0MRP6
	SMARCA1	NM_003069.5		c.3068_3071delTTGA	p.Ile1023ArgfsTer25	frameshift	Exon 24 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.3068_3071delTTGA	p.Ile1023ArgfsTer45	frameshift	Exon 24 of 25	ENSP00000360162.4	B7ZLQ5
	SMARCA1	ENST00000371123.5	TSL:1	c.3032_3035delTTGA	p.Ile1011ArgfsTer45	frameshift	Exon 23 of 24	ENSP00000360164.2	A0A0A0MRP6
	SMARCA1	ENST00000371122.8	TSL:1	c.3068_3071delTTGA	p.Ile1023ArgfsTer25	frameshift	Exon 24 of 25	ENSP00000360163.4	P28370-1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chrX-128582379;