rs1409607754

Positions:

• chrX-48688808-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000377.3(WAS):​c.1080A>C​(p.Pro360Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 0 hem., cov: 12)
  • Exomes 𝑓: 0.00042 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: WAS NM_000377.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.0100

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-48688808-A-C is Benign according to our data. Variant chrX-48688808-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437265.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-0.01 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WAS	NM_000377.3	c.1080A>C	p.Pro360Pro	synonymous_variant	10/12	ENST00000376701.5	NP_000368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WAS	ENST00000376701.5	c.1080A>C	p.Pro360Pro	synonymous_variant	10/12	1	NM_000377.3	ENSP00000365891.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 80 AN: 50322 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 12600 FAILED QC

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.000803

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.00297

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000416 AC: 260 AN: 625176 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 180036

Gnomad4 AFR exome AF: 0.000600

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.000914

Gnomad4 EAS exome AF: 0.000924

Gnomad4 SAS exome AF: 0.000368

Gnomad4 FIN exome AF: 0.000941

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.000773

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00161 AC: 81 AN: 50340 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 12606

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.00168

Gnomad4 ASJ AF: 0.000803

Gnomad4 EAS AF: 0.00180

Gnomad4 SAS AF: 0.00298

Gnomad4 FIN AF: 0.00329

Gnomad4 NFE AF: 0.00155

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0506 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	WAS: BP4, BP7 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 09, 2016

- -

Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1409607754; hg19: chrX-48547197; COSMIC: COSV64997936; COSMIC: COSV64997936;