NM_139281.3:c.-78C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_139281.3(WDR36):​c.-78C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,614,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

WDR36
NM_139281.3 5_prime_UTR

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.542
Variant links:
Genes affected
WDR36 (HGNC:30696): (WD repeat domain 36) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations in this gene have been associated with adult-onset primary open-angle glaucoma (POAG). [provided by RefSeq, Jul 2008]

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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=0.043596715).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WDR36NM_139281.3 linkc.-78C>A 5_prime_UTR_variant Exon 1 of 23 ENST00000513710.4 NP_644810.2 Q8NI36
WDR36XM_047416729.1 linkc.-78C>A 5_prime_UTR_variant Exon 1 of 21 XP_047272685.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WDR36ENST00000513710 linkc.-78C>A 5_prime_UTR_variant Exon 1 of 23 1 NM_139281.3 ENSP00000424628.3 A0A0A0MTB8
WDR36ENST00000505303.5 linkn.59C>A non_coding_transcript_exon_variant Exon 1 of 15 5
WDR36ENST00000515784.1 linkn.33C>A non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.000250
AC:
38
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
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:
0.000353
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000259
AC:
65
AN:
251316
Hom.:
0
AF XY:
0.000235
AC XY:
32
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.000173
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:
0.000466
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000363
AC:
531
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.000360
AC XY:
262
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000441
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
AF:
0.000249
AC:
38
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.000255
AC XY:
19
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000404
Hom.:
0
Bravo
AF:
0.000348
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000239
AC:
29
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jun 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with glaucoma (PMID: 17563723, 18172102). This variant is present in population databases (rs148041801, gnomAD 0.05%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 31 of the WDR36 protein (p.Pro31Thr). -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
5.3
DANN
Uncertain
0.98
DEOGEN2
Benign
0.053
T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.38
N
LIST_S2
Benign
0.37
.;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.070
N;.
REVEL
Uncertain
0.31
Polyphen
0.0
B;B
Vest4
0.69
MVP
0.90
MPC
0.030
ClinPred
0.0091
T
GERP RS
-2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.056
gMVP
0.14

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: rs148041801; hg19: chr5-110428077; API