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rs369748157

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001163809.2(WDR81):c.3115G>A(p.Ala1039Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,587,240 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1039P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

WDR81
NM_001163809.2 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.0550
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013326347).
BP6
Variant 17-1728074-G-A is Benign according to our data. Variant chr17-1728074-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377255.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WDR81NM_001163809.2 linkuse as main transcriptc.3115G>A p.Ala1039Thr missense_variant 1/10 ENST00000409644.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WDR81ENST00000409644.6 linkuse as main transcriptc.3115G>A p.Ala1039Thr missense_variant 1/101 NM_001163809.2 P1Q562E7-1
ENST00000576540.1 linkuse as main transcriptn.296-2163C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000374
AC:
57
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000661
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000276
AC:
56
AN:
203016
Hom.:
0
AF XY:
0.000307
AC XY:
34
AN XY:
110718
show subpopulations
Gnomad AFR exome
AF:
0.000260
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000279
Gnomad NFE exome
AF:
0.000544
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000451
AC:
647
AN:
1434898
Hom.:
4
Cov.:
34
AF XY:
0.000420
AC XY:
299
AN XY:
711934
show subpopulations
Gnomad4 AFR exome
AF:
0.000213
Gnomad4 AMR exome
AF:
0.0000250
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000259
Gnomad4 NFE exome
AF:
0.000551
Gnomad4 OTH exome
AF:
0.000337
GnomAD4 genome
AF:
0.000374
AC:
57
AN:
152342
Hom.:
0
Cov.:
33
AF XY:
0.000362
AC XY:
27
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000662
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000478
Hom.:
0
Bravo
AF:
0.000329
ESP6500AA
AF:
0.000233
AC:
1
ESP6500EA
AF:
0.000353
AC:
3
ExAC
AF:
0.000192
AC:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 18, 2018This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 03, 2022The c.3115G>A (p.A1039T) alteration is located in exon 1 (coding exon 1) of the WDR81 gene. This alteration results from a G to A substitution at nucleotide position 3115, causing the alanine (A) at amino acid position 1039 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 15, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.74
Cadd
Benign
0.035
Dann
Benign
0.81
DEOGEN2
Benign
0.013
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.61
T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.38
N
REVEL
Benign
0.027
Sift
Benign
0.50
T
Sift4G
Benign
0.13
T
Vest4
0.026
MVP
0.030
MPC
0.38
ClinPred
0.0088
T
GERP RS
-8.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.021
gMVP
0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369748157; hg19: chr17-1631368; API