X-48684373-G-A

Variant names:

• chrX-48684373-G-A
• rs782290433
• NM_000377.3:c.223G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000377.3(WAS):​c.223G>A​(p.Val75Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000895 in 111,733 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000322003: Functional studies have shown that V75M causes a severe negative effect on WAS protein function by interfering with WAS SUMOylation (Sarkar et al., 2015)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V75V) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
• Consequence: WAS NM_000377.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.46
• Publications: 22 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322003: Functional studies have shown that V75M causes a severe negative effect on WAS protein function by interfering with WAS SUMOylation (Sarkar et al., 2015).; SCV000696641: Functional studies, Rajmohan_2009 and Sarkar_2015, indicate that the varaint does impact WAS protein functionality.; SCV006585427: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 26261240)."; SCV000899091: Functional studies have shown a deleterious effect of this variant (Albert 2010 PMID:20173115, Sarkar 2015 PMID:26261240).; SCV000945682: Experimental studies have shown that this missense change affects WAS function (PMID: 19817875, 26261240).
• PM1: In a hotspot region, there are 3 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-48684373-G-A is Pathogenic according to our data. Variant chrX-48684373-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 265289.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.223G>A	p.Val75Met	missense	Exon 2 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.223G>A	p.Val75Met	missense	Exon 2 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.223G>A	p.Val75Met	missense	Exon 2 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.223G>A	p.Val75Met	missense	Exon 2 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.223G>A	p.Val75Met	missense	Exon 2 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.223G>A	p.Val75Met	missense	Exon 2 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111682 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182289 AF XY: 0.00

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111733 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33899

African (AFR) AF: 0.0000326 AC: 1 AN: 30712

American (AMR) AF: 0.00 AC: 0 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53079

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.0000727 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (3)
2	-	-	not provided (2)
2	-	-	Thrombocytopenia 1 (2)
1	-	-	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.92		Loss of methylation at K76 (P = 0.0286)
MVP		1.0
MPC		1.6
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.92
gMVP		0.96
Mutation Taster		=69/31	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: rs782290433; hg19: chrX-48542762; COSMIC: COSV64996692; COSMIC: COSV64996692;