Genetic Variant WAS:c.1453+16C>T (chrX-48689450-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000377.3(WAS):c.1453+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,188,626 control chromosomes in the GnomAD database, including 1 homozygotes. There are 522 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., 28 hem., cov: 23)

Exomes 𝑓: 0.0015 ( 0 hom. 494 hem. )

Consequence

WAS
NM_000377.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.332

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant X-48689450-C-T is Benign according to our data. Variant chrX-48689450-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (129/110937) while in subpopulation NFE AF = 0.00193 (102/52929). AF 95% confidence interval is 0.00162. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 129 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000377.3. 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.1453+16C>T	intron	N/A	NP_000368.1	P42768
WAS	NM_001438877.1		c.1453+16C>T	intron	N/A	NP_001425806.1
WAS	NM_001438878.1		c.1297+16C>T	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.1453+16C>T	intron	N/A	ENSP00000365891.4	P42768
WAS	ENST00000698635.1		c.1453+16C>T	intron	N/A	ENSP00000513850.1	A0A8V8TM35
WAS	ENST00000698626.1		c.1453+16C>T	intron	N/A	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

129

AN:

110882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00106

Gnomad ASJ

AF:

0.000757

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000380

Gnomad FIN

AF:

0.000340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00145

AC:

230

AN:

158738

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.000357

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00144

Gnomad EAS exome

AF:

0.00113

Gnomad FIN exome

AF:

0.0000700

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00151

AC:

1622

AN:

1077689

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

494

AN XY:

345833

show subpopulations

African (AFR)

AF:

0.0000766

AC:

AN:

26117

American (AMR)

AF:

0.000893

AC:

AN:

33592

Ashkenazi Jewish (ASJ)

AF:

0.00105

AC:

AN:

19024

East Asian (EAS)

AF:

0.000402

AC:

AN:

29831

South Asian (SAS)

AF:

0.000481

AC:

AN:

51962

European-Finnish (FIN)

AF:

0.000176

AC:

AN:

39683

Middle Eastern (MID)

AF:

0.00955

AC:

AN:

4083

European-Non Finnish (NFE)

AF:

0.00169

AC:

1396

AN:

828017

Other (OTH)

AF:

0.00201

AC:

AN:

45380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00116

AC:

129

AN:

110937

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

AN XY:

33157

show subpopulations

African (AFR)

AF:

0.000197

AC:

AN:

30507

American (AMR)

AF:

0.00105

AC:

AN:

10436

Ashkenazi Jewish (ASJ)

AF:

0.000757

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3515

South Asian (SAS)

AF:

0.000381

AC:

AN:

2626

European-Finnish (FIN)

AF:

0.000340

AC:

AN:

5875

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00193

AC:

102

AN:

52929

Other (OTH)

AF:

0.00331

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00142

Hom.:

Bravo

AF:

0.00116

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wiskott-Aldrich syndrome;C1839163:Thrombocytopenia 1;C1845987:X-linked severe congenital neutropenia (2)

not provided (1)

not specified (1)

Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.8

(source)

DANN

Benign

0.56

PhyloP100

0.33

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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