X-48684427-AC-ACCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0540

Publications

3 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
X-linked severe congenital neutropenia
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
thrombocytopenia 1
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

WAS links:

ENSG00000232828 (HGNC:):

ENSG00000232828 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WAS	NM_000377.3	MANE Select	c.273+10_273+11dupCC	intron	N/A	NP_000368.1	P42768
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

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

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

247

AN:

107101

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00202

AC XY:

716

AN XY:

353868

show subpopulations

African (AFR)

AF:

0.0000385

AC:

AN:

25990

American (AMR)

AF:

0.00

AC:

AN:

33941

Ashkenazi Jewish (ASJ)

AF:

0.0000522

AC:

AN:

19155

East Asian (EAS)

AF:

0.0684

AC:

1999

AN:

29219

South Asian (SAS)

AF:

0.00177

AC:

AN:

52488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39407

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000455

AC:

AN:

836070

Other (OTH)

AF:

0.00314

AC:

143

AN:

45586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00228

AC:

244

AN:

107142

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

AN XY:

30332

show subpopulations

African (AFR)

AF:

0.000102

AC:

AN:

29271

American (AMR)

AF:

0.000300

AC:

AN:

10000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2588

East Asian (EAS)

AF:

0.0672

AC:

222

AN:

3305

South Asian (SAS)

AF:

0.00248

AC:

AN:

2423

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.000135

AC:

AN:

51725

Other (OTH)

AF:

0.00208

AC:

AN:

1444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000406

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

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)

(source)

Splicing

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over