17-1724990-G-A

Variant summary

Our verdict is Likely benign. Variant got -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. 16/21 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

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.709
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0643338).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR81NM_001163809.2 linkuse as main transcriptc.31G>A p.Ala11Thr missense_variant 1/10 ENST00000409644.6 NP_001157281.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR81ENST00000409644.6 linkuse as main transcriptc.31G>A p.Ala11Thr missense_variant 1/101 NM_001163809.2 ENSP00000386609 P1Q562E7-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152192
Hom.:
0
Cov.:
33
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
GnomAD3 exomes
AF:
0.0000445
AC:
3
AN:
67348
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
35388
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 SAS 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:
5
AN:
1311138
Hom.:
0
Cov.:
75
AF XY:
0.00000156
AC XY:
1
AN XY:
639788
show subpopulations
Gnomad4 AFR exome
AF:
0.0000700
Gnomad4 AMR exome
AF:
0.0000436
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000288
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.59e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2023The c.31G>A (p.A11T) 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 31, causing the alanine (A) at amino acid position 11 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
1.2
DANN
Benign
0.90
DEOGEN2
Benign
0.012
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.43
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.064
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.34
N
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.040
N
REVEL
Benign
0.010
Sift
Benign
0.26
T
Sift4G
Benign
0.50
T
Vest4
0.12
MutPred
0.22
Gain of phosphorylation at A11 (P = 0.0079);
MVP
0.40
MPC
0.38
ClinPred
0.015
T
GERP RS
-5.1
Varity_R
0.025
gMVP
0.23

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: rs1037264776; hg19: chr17-1628284; API