rs387906717

Variant names:

• chrX-48688403-T-C
• rs387906717
• NM_000377.3:c.881T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000377.3(WAS):​c.881T>C​(p.Ile294Thr) variant causes a missense change involving the alteration of a 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 (★★). ClinVar reports functional evidence for this variant: "SCV003845967: Functional studies also demonstrated that the p.Ile294Thr substitution affects the normal function of the WAS protein (Beel K,et,al.,2008)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. I294I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.36
• Publications: 30 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003845967: Functional studies also demonstrated that the p.Ile294Thr substitution affects the normal function of the WAS protein (Beel K,et,al.,2008).; SCV005086454: "This variant has moderate functional evidence supporting abnormal protein function. Mutant protein expressed in vitro showed an increased capacity to stimulate actin polymerisation (PMID: 16804117)."; SCV001223565: Experimental studies have shown that this missense change affects WAS function (PMID: 16804117, 19006568).; SCV002069300: Functional studies also demonstrated that the p.Ile294Thr substitution affects the normal function of the WAS protein (PMID: 19006568).; SCV004109242: Functional studies have shown that this variant impacts protein function (Rajmohan et al. 2009. PubMed ID: 19817875; Moulding et al. 2007. PubMed ID: 17724125).; SCV005394748: The most pronounced variant effect results in impaired myelopoiesis and increased levels of hematopoietic cell apoptosis in a liquid culture system (Ancliff_2006). PMID: 16804117, 19006568
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-48688403-T-C is Pathogenic according to our data. Variant chrX-48688403-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.881T>C	p.Ile294Thr	missense	Exon 9 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.881T>C	p.Ile294Thr	missense	Exon 9 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.881T>C	p.Ile294Thr	missense	Exon 9 of 12	NP_001425807.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.881T>C	p.Ile294Thr	missense	Exon 9 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.881T>C	p.Ile294Thr	missense	Exon 9 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.881T>C	p.Ile294Thr	missense	Exon 9 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	X-linked severe congenital neutropenia (5)
2	-	-	not provided (2)
1	-	-	WAS-related disorder (1)
1	-	-	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (1)
1	-	-	X-Linked Neutropenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.90		Gain of disorder (P = 0.039)
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.96
Mutation Taster		=11/89	disease causing (ClinVar)

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

dbSNP: rs387906717; hg19: chrX-48546792;