X-48684427-AC-ACCCC

Variant names:

• chrX-48684427-A-ACCC
• rs58371799
• NM_000377.3:c.273+9_273+11dupCCC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The ENST00000376701.5(WAS):​c.273+4_273+5insCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,086,013 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: WAS ENST00000376701.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• X-linked severe congenital neutropenia

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant X-48684427-A-ACCC is Benign according to our data. Variant chrX-48684427-A-ACCC is described in ClinVar as Likely_benign. ClinVar VariationId is 2148676.Status of the report is criteria_provided_single_submitter, 1 stars.

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+9_273+11dupCCC		intron	N/A	NP_000368.1
	WAS	NM_001438877.1		c.273+9_273+11dupCCC		intron	N/A	NP_001425806.1
	WAS	NM_001438878.1		c.273+9_273+11dupCCC		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+5insCCC		splice_region intron	N/A	ENSP00000365891.4
	WAS	ENST00000698635.1		c.273+4_273+5insCCC		splice_region intron	N/A	ENSP00000513850.1
	WAS	ENST00000698626.1		c.273+4_273+5insCCC		splice_region intron	N/A	ENSP00000513845.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 161608 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 6 AN: 1086013 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 1 AN XY: 353893

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25990

American (AMR) AF: 0.00 AC: 0 AN: 33941

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19155

East Asian (EAS) AF: 0.000205 AC: 6 AN: 29255

South Asian (SAS) AF: 0.00 AC: 0 AN: 52490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39407

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836074

Other (OTH) AF: 0.00 AC: 0 AN: 45591

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000181504), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 51

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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

Splicing

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

Other links and lift over

dbSNP: rs58371799; hg19: chrX-48542816;