chrX-48684323-C-A

Position:

• chrX-48684323-C-A

Variant summary

Our verdict is Pathogenic. Variant got 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. P58L) has been classified as Likely 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain WH1 (size 109) in uniprot entity WASP_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• 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 id is 420291.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.173C>A	p.Pro58His	missense_variant	2/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.173C>A	p.Pro58His	missense_variant	2/12	1	NM_000377.3	ENSP00000365891	P2

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2017

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 v4.3

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;D
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.78
MutPred		0.74		Gain of helix (P = 0.0496);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs132630275; hg19: chrX-48542712;