chrX-48683869-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000377.3(WAS):c.16A>G(p.Met6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,536 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 6 hem. )

Consequence

WAS
NM_000377.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.407

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08142796).

BP6

Variant X-48683869-A-G is Benign according to our data. Variant chrX-48683869-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1685211.

BS2

High AC in GnomAdExome4 at 12 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	HGVSp	Effect	Exon Rank	Protein	UniProt
WAS	NM_000377.3	MANE Select	c.16A>G	p.Met6Val	missense	Exon 1 of 12	NP_000368.1	P42768
WAS	NM_001438877.1		c.16A>G	p.Met6Val	missense	Exon 1 of 12	NP_001425806.1
WAS	NM_001438878.1		c.16A>G	p.Met6Val	missense	Exon 1 of 12	NP_001425807.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WAS	ENST00000376701.5	TSL:1 MANE Select	c.16A>G	p.Met6Val	missense	Exon 1 of 12	ENSP00000365891.4	P42768
WAS	ENST00000698635.1		c.16A>G	p.Met6Val	missense	Exon 1 of 12	ENSP00000513850.1	A0A8V8TM35
WAS	ENST00000698626.1		c.16A>G	p.Met6Val	missense	Exon 1 of 13	ENSP00000513845.1	A0A8V8TNH9

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111481

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

183053

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1098000

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.000148

AC:

AN:

54127

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841974

Other (OTH)

AF:

0.00

AC:

AN:

46077

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111536

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30745

American (AMR)

AF:

0.00

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3505

South Asian (SAS)

AF:

0.00

AC:

AN:

2656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000566

AC:

AN:

52961

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (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

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.17

CADD

Benign

0.93

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.011

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.081

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

-0.92

PhyloP100

0.41

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.75

REVEL

Uncertain

0.44

Sift

Benign

0.32

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.065

MutPred

0.33

Loss of MoRF binding (P = 0.1254)

MVP

0.84

MPC

0.59

ClinPred

0.010

GERP RS

2.4

PromoterAI

0.14

Neutral

(source)

Varity_R

0.10

gMVP

0.61

Mutation Taster

=97/3

polymorphism

(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