Genetic Variant NM_003941.4:c.564G>C (chr7-123696644-C-G) – 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.564G>C(p.Lys188Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,603,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K188K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

WASL
NM_003941.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

2 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=0.2352103).

BS2

High AC in GnomAdExome4 at 10 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.564G>C	p.Lys188Asn	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.564G>C	p.Lys188Asn	missense	Exon 6 of 11	ENSP00000223023.4	O00401
WASL	ENST00000924343.1		c.564G>C	p.Lys188Asn	missense	Exon 6 of 11	ENSP00000594402.1
WASL	ENST00000924344.1		c.477G>C	p.Lys159Asn	missense	Exon 5 of 10	ENSP00000594403.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245000

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000634

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1451556

Hom.:

Cov.:

AF XY:

0.00000970

AC XY:

AN XY:

721982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32990

American (AMR)

AF:

0.00

AC:

AN:

43622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

38936

South Asian (SAS)

AF:

0.00

AC:

AN:

84526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000903

AC:

AN:

1106838

Other (OTH)

AF:

0.00

AC:

AN:

59882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

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:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67912

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.24

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.1

PhyloP100

2.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.49

Sift

Benign

0.067

Sift4G

Benign

0.12

Polyphen

0.14

Vest4

0.34

MutPred

0.27

Loss of methylation at K188 (P = 0.0128)

MVP

0.73

MPC

0.50

ClinPred

0.81

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.57

Mutation Taster

=40/60

disease causing

(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