X-48684427-AC-ACC

Variant names:

• chrX-48684427-A-AC
• rs58371799
• NM_000377.3:c.273+11dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000376701.5(WAS):​c.273+4_273+5insC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,193,093 control chromosomes in the GnomAD database, including 123 homozygotes. There are 6,039 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (25 hom., 492 hem., cov: 21)
  • Exomes 𝑓: 0.016 (98 hom. 5547 hem.)
• Consequence: WAS ENST00000376701.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0540
• Publications: 3 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: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked severe congenital neutropenia

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-48684427-A-AC is Benign according to our data. Variant chrX-48684427-A-AC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0192 (2057/107140) while in subpopulation AFR AF = 0.0312 (914/29267). AF 95% confidence interval is 0.0296. There are 25 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2057 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376701.5. 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.273+11dupC		intron	N/A	NP_000368.1	P42768
	WAS	NM_001438877.1		c.273+11dupC		intron	N/A	NP_001425806.1
	WAS	NM_001438878.1		c.273+11dupC		intron	N/A	NP_001425807.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAS	ENST00000376701.5	TSL:1 MANE Select	c.273+4_273+5insC		splice_region intron	N/A	ENSP00000365891.4	P42768
	WAS	ENST00000698635.1		c.273+4_273+5insC		splice_region intron	N/A	ENSP00000513850.1	A0A8V8TM35
	WAS	ENST00000698626.1		c.273+4_273+5insC		splice_region intron	N/A	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2046 AN: 107099 Hom.: 23 Cov.: 21

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.00991

Gnomad ASJ AF: 0.0128

Gnomad EAS AF: 0.00150

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.0137 AC: 2214 AN: 161608 AF XY: 0.0123

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00776

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.00226

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0160 AC: 17385 AN: 1085953 Hom.: 98 Cov.: 32 AF XY: 0.0157 AC XY: 5547 AN XY: 353855

African (AFR) AF: 0.0323 AC: 839 AN: 25989

American (AMR) AF: 0.00793 AC: 269 AN: 33940

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 305 AN: 19155

East Asian (EAS) AF: 0.00260 AC: 76 AN: 29246

South Asian (SAS) AF: 0.0139 AC: 728 AN: 52489

European-Finnish (FIN) AF: 0.0114 AC: 448 AN: 39400

Middle Eastern (MID) AF: 0.0163 AC: 67 AN: 4110

European-Non Finnish (NFE) AF: 0.0167 AC: 13934 AN: 836036

Other (OTH) AF: 0.0158 AC: 719 AN: 45588

GnomAD4 genome AF: 0.0192 AC: 2057 AN: 107140 Hom.: 25 Cov.: 21 AF XY: 0.0162 AC XY: 492 AN XY: 30328

African (AFR) AF: 0.0312 AC: 914 AN: 29267

American (AMR) AF: 0.00990 AC: 99 AN: 10000

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 33 AN: 2588

East Asian (EAS) AF: 0.00151 AC: 5 AN: 3312

South Asian (SAS) AF: 0.0186 AC: 45 AN: 2423

European-Finnish (FIN) AF: 0.00980 AC: 54 AN: 5512

Middle Eastern (MID) AF: 0.0190 AC: 4 AN: 211

European-Non Finnish (NFE) AF: 0.0165 AC: 852 AN: 51720

Other (OTH) AF: 0.0277 AC: 40 AN: 1444

Alfa AF: 0.00724 Hom.: 51

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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		-0.054
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58371799;

hg19: chrX-48542816;