NM_000377.3:c.173C>A

Variant names:

• chrX-48684323-C-A
• rs132630275
• NM_000377.3:c.173C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000377.3(WAS):​c.173C>A​(p.Pro58His) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.98
• Publications: 5 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• X-linked severe congenital neutropenia

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000377.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48684323-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11126.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant X-48684323-C-A is Pathogenic according to our data. Variant chrX-48684323-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 420291.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	NM_000377.3	MANE Select	c.173C>A	p.Pro58His	missense	Exon 2 of 12	NP_000368.1
	WAS	NM_001438877.1		c.173C>A	p.Pro58His	missense	Exon 2 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.173C>A	p.Pro58His	missense	Exon 2 of 12	NP_001425807.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.173C>A	p.Pro58His	missense	Exon 2 of 12	ENSP00000365891.4
	WAS	ENST00000698635.1		c.173C>A	p.Pro58His	missense	Exon 2 of 12	ENSP00000513850.1
	WAS	ENST00000698626.1		c.173C>A	p.Pro58His	missense	Exon 2 of 13	ENSP00000513845.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 14, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

To our knowledge, the P58H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P58H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the WH1 domain that is conserved in mammals; the WH1 domain has been shown to be critical for cellular processes utilizing actin (Veltman et al., 2010). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same codon (P58A/R/L) and in nearby residues (A56T/V) have been reported in the Human Gene Mutation Database in association with WAS-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.83
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.74		Gain of helix (P = 0.0496)
MVP		0.96
MPC		1.7
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.77
gMVP		0.97
Mutation Taster		=13/87	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: rs132630275; hg19: chrX-48542712;