rs193922412

Variant names:

• chrX-48688910-ACCACCACCG-A
• rs193922412
• NM_000377.3:c.1197_1205delACCGCCACC

Your query was ambiguous. Multiple possible variants found:

• chrX-48688910-ACCACCACCG-A
• chrX-48688910-ACCACCACCG-ACCACCACCGCCACCACCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000377.3(WAS):​c.1197_1205delACCGCCACC​(p.Pro400_Pro402del) variant causes a disruptive 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). Synonymous variant affecting the same amino acid position (i.e. P399P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.00023 (0 hom. 66 hem.)
• Consequence: WAS NM_000377.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.88
• Publications: 0 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: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked severe congenital neutropenia

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 36908.
• 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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 XL,AD gene.

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.1197_1205delACCGCCACC	p.Pro400_Pro402del	disruptive_inframe_deletion	Exon 10 of 12	NP_000368.1	P42768
	WAS	NM_001438877.1		c.1197_1205delACCGCCACC	p.Pro400_Pro402del	disruptive_inframe_deletion	Exon 10 of 12	NP_001425806.1
	WAS	NM_001438878.1		c.1041_1049delACCGCCACC	p.Pro348_Pro350del	disruptive_inframe_deletion	Exon 10 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.1197_1205delACCGCCACC	p.Pro400_Pro402del	disruptive_inframe_deletion	Exon 10 of 12	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.1197_1205delACCGCCACC	p.Pro400_Pro402del	disruptive_inframe_deletion	Exon 10 of 12	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.1197_1205delACCGCCACC	p.Pro400_Pro402del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.000150 AC: 15 AN: 100112 Hom.: 0 Cov.: 21

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

GnomAD2 exomes AF: 0.000163 AC: 17 AN: 104064 AF XY: 0.000132

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 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

African (AFR) AF: 0.000122 AC: 3 AN: 24605

American (AMR) AF: 0.000215 AC: 6 AN: 27878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17190

East Asian (EAS) AF: 0.0000384 AC: 1 AN: 26060

South Asian (SAS) AF: 0.000251 AC: 12 AN: 47722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3027

European-Non Finnish (NFE) AF: 0.000260 AC: 209 AN: 804262

Other (OTH) AF: 0.000141 AC: 6 AN: 42602

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

African (AFR) AF: 0.00 AC: 0 AN: 27037

American (AMR) AF: 0.000105 AC: 1 AN: 9513

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2488

East Asian (EAS) AF: 0.00 AC: 0 AN: 2895

South Asian (SAS) AF: 0.00 AC: 0 AN: 1997

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.000285 AC: 14 AN: 49208

Other (OTH) AF: 0.00 AC: 0 AN: 1364

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.000196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=186/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs193922412; hg19: chrX-48547299; COSMIC: COSV105927051;