Genetic Variant WASL:p.Pro177Leu (chr7-123696678-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003941.4(WASL):c.530C>T(p.Pro177Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000811 in 1,603,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

WASL
NM_003941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.63

Publications

1 publications found

Variant links:

Genes affected

WASL (HGNC:12735): (WASP like actin nucleation promoting factor) This gene encodes a member of the Wiskott-Aldrich syndrome (WAS) protein family. Wiskott-Aldrich syndrome proteins share similar domain structure, and associate with a variety of signaling molecules to alter the actin cytoskeleton. The encoded protein is highly expressed in neural tissues, and interacts with several proteins involved in cytoskeletal organization, including cell division control protein 42 (CDC42) and the actin-related protein-2/3 (ARP2/3) complex. The encoded protein may be involved in the formation of long actin microspikes, and in neurite extension. [provided by RefSeq, Jul 2013]

WASL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14974985).

BS2

High AC in GnomAdExome4 at 128 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003941.4. 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
	WASL	NM_003941.4	MANE Select	c.530C>T	p.Pro177Leu	missense	Exon 6 of 11	NP_003932.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WASL	ENST00000223023.5	TSL:1 MANE Select	c.530C>T	p.Pro177Leu	missense	Exon 6 of 11	ENSP00000223023.4	O00401
WASL	ENST00000924343.1		c.530C>T	p.Pro177Leu	missense	Exon 6 of 11	ENSP00000594402.1
WASL	ENST00000924344.1		c.443C>T	p.Pro148Leu	missense	Exon 5 of 10	ENSP00000594403.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151844

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

245704

AF XY:

0.0000225

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:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000882

AC:

128

AN:

1451624

Hom.:

Cov.:

AF XY:

0.0000859

AC XY:

AN XY:

722054

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33060

American (AMR)

AF:

0.00

AC:

AN:

43718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25890

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.00

AC:

AN:

84398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000105

AC:

116

AN:

1106828

Other (OTH)

AF:

0.000184

AC:

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000132

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41344

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000169

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.20

Eigen

Benign

-0.19

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

M_CAP

Benign

0.047

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

0.41

PhyloP100

5.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.35

Sift

Benign

0.29

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.26

MVP

0.19

MPC

0.43

ClinPred

0.14

GERP RS

6.0

Varity_R

0.075

gMVP

0.33

Mutation Taster

=85/15

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

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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