rs235422

Variant names:

• chrX-48683512-T-C
• rs235422
• NM_001438879.1:c.-34-308T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001438879.1(WAS):​c.-34-308T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 204,149 control chromosomes in the GnomAD database, including 91 homozygotes. There are 723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (79 hom., 681 hem., cov: 22)
  • Exomes 𝑓: 0.0035 (12 hom. 42 hem.)
• Consequence: WAS NM_001438879.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.177
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-48683512-T-C is Benign according to our data. Variant chrX-48683512-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265197.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438879.1. 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_001438879.1		c.-34-308T>C		intron	N/A	NP_001425808.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000698625.1		c.-34-308T>C		intron	N/A	ENSP00000513844.1	P42768
	WAS	ENST00000906191.1		c.-35+285T>C		intron	N/A	ENSP00000576250.1
	WAS	ENST00000906192.1		c.-35+285T>C		intron	N/A	ENSP00000576251.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 2605 AN: 111756 Hom.: 78 Cov.: 22

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.0152

GnomAD4 exome AF: 0.00351 AC: 324 AN: 92342 Hom.: 12 AF XY: 0.00235 AC XY: 42 AN XY: 17866

African (AFR) AF: 0.0751 AC: 259 AN: 3448

American (AMR) AF: 0.00613 AC: 25 AN: 4080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2985

East Asian (EAS) AF: 0.00 AC: 0 AN: 7046

South Asian (SAS) AF: 0.000165 AC: 1 AN: 6061

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4243

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 343

European-Non Finnish (NFE) AF: 0.000138 AC: 8 AN: 58022

Other (OTH) AF: 0.00507 AC: 31 AN: 6114

GnomAD4 genome AF: 0.0233 AC: 2605 AN: 111807 Hom.: 79 Cov.: 22 AF XY: 0.0200 AC XY: 681 AN XY: 34009

African (AFR) AF: 0.0809 AC: 2480 AN: 30673

American (AMR) AF: 0.00834 AC: 88 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.000736 AC: 2 AN: 2719

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53113

Other (OTH) AF: 0.0150 AC: 23 AN: 1531

Alfa AF: 0.00700 Hom.: 163

Bravo AF: 0.0268

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.84
PhyloP100		0.18
PromoterAI		-0.039	Neutral

Splicing

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

Other links and lift over

dbSNP: rs235422; hg19: chrX-48541901;