chr17-1731098-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000446363.5(WDR81):c.-87C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000372 in 1,612,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

WDR81
ENST00000446363.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.57

Publications

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

WDR81 links:

ENSG00000262791 (HGNC:58142):

ENSG00000262791 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.46

PP5

Variant 17-1731098-C-T is Pathogenic according to our data. Variant chr17-1731098-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000446363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR81	NM_001163809.2	MANE Select	c.3997C>T	p.Arg1333*	stop_gained	Exon 4 of 10	NP_001157281.1
WDR81	NM_152348.4		c.844C>T	p.Arg282*	stop_gained	Exon 5 of 11	NP_689561.2
WDR81	NM_001163673.2		c.388C>T	p.Arg130*	stop_gained	Exon 4 of 10	NP_001157145.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR81	ENST00000446363.5	TSL:1	c.-87C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000401560.1
WDR81	ENST00000409644.6	TSL:1 MANE Select	c.3997C>T	p.Arg1333*	stop_gained	Exon 4 of 10	ENSP00000386609.1
WDR81	ENST00000446363.5	TSL:1	c.-87C>T		5_prime_UTR	Exon 3 of 9	ENSP00000401560.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000807

AC:

AN:

247938

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000125

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:

0.00000342

AC:

AN:

1460584

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111886

Other (OTH)

AF:

0.0000166

AC:

AN:

60348

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

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:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000778

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2

Pathogenic:3

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Dec 21, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Inborn genetic diseases

Pathogenic:1

Nov 01, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3997C>T (p.R1333*) alteration, located in exon 4 (coding exon 4) of the WDR81 gene, consists of a C to T substitution at nucleotide position 3997. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1333. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/247938) total alleles studied. The highest observed frequency was 0.013% (2/15940) of African alleles. This variant has been identified in the homozygous state in individual(s) with features consistent with WDR81-related brain malformations (Komara, 2016; Trujillano, 2017). Based on the available evidence, this alteration is classified as pathogenic.

not provided

Pathogenic:1

Oct 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33724704, 31345219, 27535533, 26437881)

Cerebellar ataxia

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1,PM2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.6

Vest4

0.41

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over