X-48686928-CT-GA

Variant names:

• chrX-48686928-CT-GA
• NM_000377.3:c.707_708delCTinsGA
• WAS p.Ala236Gly

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_000377.3(WAS):​c.707_708delCTinsGA​(p.Ala236Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A236T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.39
• Publications: 0 publications found

Genes affected

WAS (HGNC:12731): (WASP actin nucleation promoting factor) The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]

WAS Gene-Disease associations (from GenCC):

• Wiskott-Aldrich syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• X-linked severe congenital neutropenia

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• thrombocytopenia 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_000377.3 (WAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000377.3. 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
	WAS	NM_000377.3	MANE Select	c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	NP_000368.1	P42768
	WAS	NM_001438877.1		c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	NP_001425806.1
	WAS	NM_001438878.1		c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	NP_001425807.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.707_708delCTinsGA	p.Ala236Gly	missense	N/A	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-48545317;