rs193922412

chrX-48688910-ACCACCACCG-AchrX-48688910-ACCACCACCG-ACCACCACCGCCACCACCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000377.3(WAS):c.1197_1205del(p.Pro402_Pro404del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000224 in 1,127,312 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 67 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.00023 (0 hom. 66 hem.)
• Consequence: WAS NM_000377.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.88

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 Benign. Variant got -9 ACMG points.

• BP6: Variant X-48688910-ACCACCACCG-A is Benign according to our data. Variant chrX-48688910-ACCACCACCG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36908.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00015 (15/100128) while in subpopulation NFE AF= 0.000285 (14/49208). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAS	NM_000377.3	c.1197_1205del	p.Pro402_Pro404del	inframe_deletion	10/12	ENST00000376701.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAS	ENST00000376701.5	c.1197_1205del	p.Pro402_Pro404del	inframe_deletion	10/12	1	NM_000377.3	P2

Frequencies

GnomAD3 genomes AF: 0.000150 AC: 15 AN: 100112 Hom.: 0 Cov.: 21 AF XY: 0.0000371 AC XY: 1 AN XY: 26984

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000105

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: 0.000284

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 17 AN: 104064 Hom.: 0 AF XY: 0.000132 AC XY: 4 AN XY: 30222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 237 AN: 1027184 Hom.: 0 AF XY: 0.000203 AC XY: 66 AN XY: 325548

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000384

Gnomad4 SAS exome AF: 0.000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000141

GnomAD4 genome AF: 0.000150 AC: 15 AN: 100128 Hom.: 0 Cov.: 21 AF XY: 0.0000370 AC XY: 1 AN XY: 27012

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000285

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.000196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 01, 2017

Variant summary: The WAS c.1197_1205delACCGCCACC (p.Pro400_Pro402del) variant involves the in-frame deletion of 3 amino acids in the CRIB domain (InterPro). One in silico tool predicts a benign outcome for this variant. This variant was found in 2/9179 control chromosomes at a frequency of 0.0002179, which does not exceed the estimated maximal expected allele frequency of a pathogenic WAS variant (0.0035355). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922412; hg19: chrX-48547299;