X-48684427-AC-ACCC

Variant names:

• chrX-48684427-A-ACC
• rs58371799
• NM_000377.3:c.273+10_273+11dupCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000376701.5(WAS):​c.273+4_273+5insCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,193,108 control chromosomes in the GnomAD database, including 65 homozygotes. There are 792 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (5 hom., 76 hem., cov: 21)
  • Exomes 𝑓: 0.0021 (60 hom. 716 hem.)
• Consequence: WAS ENST00000376701.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant X-48684427-A-ACC is Benign according to our data. Variant chrX-48684427-A-ACC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

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+10_273+11dupCC		intron	N/A	NP_000368.1
	WAS	NM_001438877.1		c.273+10_273+11dupCC		intron	N/A	NP_001425806.1
	WAS	NM_001438878.1		c.273+10_273+11dupCC		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+5insCC		splice_region intron	N/A	ENSP00000365891.4
	WAS	ENST00000698635.1		c.273+4_273+5insCC		splice_region intron	N/A	ENSP00000513850.1
	WAS	ENST00000698626.1		c.273+4_273+5insCC		splice_region intron	N/A	ENSP00000513845.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 247 AN: 107101 Hom.: 5 Cov.: 21

Gnomad AFR AF: 0.000103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000300

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.00246

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00210

GnomAD2 exomes AF: 0.00521 AC: 842 AN: 161608 AF XY: 0.00472

Gnomad AFR exome AF: 0.000177

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0637

Gnomad FIN exome AF: 0.0000700

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00210 AC: 2276 AN: 1085966 Hom.: 60 Cov.: 32 AF XY: 0.00202 AC XY: 716 AN XY: 353868

African (AFR) AF: 0.0000385 AC: 1 AN: 25990

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

Ashkenazi Jewish (ASJ) AF: 0.0000522 AC: 1 AN: 19155

East Asian (EAS) AF: 0.0684 AC: 1999 AN: 29219

South Asian (SAS) AF: 0.00177 AC: 93 AN: 52488

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

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4110

European-Non Finnish (NFE) AF: 0.0000455 AC: 38 AN: 836070

Other (OTH) AF: 0.00314 AC: 143 AN: 45586

GnomAD4 genome AF: 0.00228 AC: 244 AN: 107142 Hom.: 5 Cov.: 21 AF XY: 0.00251 AC XY: 76 AN XY: 30332

African (AFR) AF: 0.000102 AC: 3 AN: 29271

American (AMR) AF: 0.000300 AC: 3 AN: 10000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2588

East Asian (EAS) AF: 0.0672 AC: 222 AN: 3305

South Asian (SAS) AF: 0.00248 AC: 6 AN: 2423

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 211

European-Non Finnish (NFE) AF: 0.000135 AC: 7 AN: 51725

Other (OTH) AF: 0.00208 AC: 3 AN: 1444

Alfa AF: 0.000406 Hom.: 51

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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

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

Other links and lift over

dbSNP: rs58371799; hg19: chrX-48542816;