Genetic Variant WDR81:p.Ala11Thr (chr17-1724990-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001163809.2(WDR81):c.31G>A(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000888 in 1,463,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

WDR81
NM_001163809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.709

Publications

0 publications found

Variant links:

Genes affected

WDR81 (HGNC:26600): (WD repeat domain 81) This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

WDR81 Gene-Disease associations (from GenCC):

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
cerebellar ataxia, intellectual disability, and dysequilibrium
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR81 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0643338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WDR81	NM_001163809.2	MANE Select	c.31G>A	p.Ala11Thr	missense	Exon 1 of 10	NP_001157281.1	Q562E7-1
WDR81	NM_152348.4		c.-123-3000G>A		intron	N/A	NP_689561.2	Q562E7-3
WDR81	NM_001163673.2		c.59-5390G>A		intron	N/A	NP_001157145.1	Q562E7-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WDR81	ENST00000409644.6	TSL:1 MANE Select	c.31G>A	p.Ala11Thr	missense	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
WDR81	ENST00000446363.5	TSL:1	c.-308-5765G>A		intron	N/A	ENSP00000401560.1	E9PDG3
WDR81	ENST00000309182.9	TSL:2	c.-123-3000G>A		intron	N/A	ENSP00000312074.5	Q562E7-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000445

AC:

AN:

67348

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000394

Gnomad AMR exome

AF:

0.0000763

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:

0.00000381

AC:

AN:

1311138

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

639788

show subpopulations

African (AFR)

AF:

0.0000700

AC:

AN:

28552

American (AMR)

AF:

0.0000436

AC:

AN:

22932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19576

East Asian (EAS)

AF:

0.0000288

AC:

AN:

34720

South Asian (SAS)

AF:

0.00

AC:

AN:

66448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4984

European-Non Finnish (NFE)

AF:

9.59e-7

AC:

AN:

1043124

Other (OTH)

AF:

0.00

AC:

AN:

54230

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

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:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.0000567

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.2

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.012

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.43

M_CAP

Benign

0.012

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

-0.71

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.040

REVEL

Benign

0.010

Sift

Benign

0.26

Sift4G

Benign

0.50

Vest4

0.12

MutPred

0.22

Gain of phosphorylation at A11 (P = 0.0079)

MVP

0.40

MPC

0.38

ClinPred

0.015

GERP RS

-5.1

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.025

gMVP

0.23

Mutation Taster

=95/5

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