chrX-48688808-A-T

Variant names:

• chrX-48688808-A-T
• NM_000377.3:c.1080A>T
• WAS p.Pro360Pro

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001438878.1(WAS):​c.932-8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_001438878.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• 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: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked severe congenital neutropenia

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438878.1. 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.1080A>T	p.Pro360Pro	synonymous	Exon 10 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.1080A>T	p.Pro360Pro	synonymous	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438879.1		c.1080A>T	p.Pro360Pro	synonymous	Exon 11 of 13	NP_001425808.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.1080A>T	p.Pro360Pro	synonymous	Exon 10 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.1080A>T	p.Pro360Pro	synonymous	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.1080A>T	p.Pro360Pro	synonymous	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 628219 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 181745

African (AFR) AF: 0.00 AC: 0 AN: 15085

American (AMR) AF: 0.00 AC: 0 AN: 14209

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8840

East Asian (EAS) AF: 0.00 AC: 0 AN: 13196

South Asian (SAS) AF: 0.00 AC: 0 AN: 30001

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22605

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1455

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 498070

Other (OTH) AF: 0.00 AC: 0 AN: 24758

GnomAD4 genome Cov.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.7
DANN	Benign	0.57
PhyloP100		-0.010

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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-48547197;