5-111092482-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139281.3(WDR36):c.26C>A(p.Thr9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: WDR36 NM_139281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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]

ACMG classification

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=0.060738236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3	c.26C>A	p.Thr9Lys	missense_variant	1/23	ENST00000513710.4
WDR36	XM_047416729.1	c.26C>A	p.Thr9Lys	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4	c.26C>A	p.Thr9Lys	missense_variant	1/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5	n.162C>A		non_coding_transcript_exon_variant	1/15	5
WDR36	ENST00000515784.1	n.136C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251064 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.000308 AC XY: 224 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74374

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.194C>A (p.T65K) alteration is located in exon 1 (coding exon 1) of the WDR36 gene. This alteration results from a C to A substitution at nucleotide position 194, causing the threonine (T) at amino acid position 65 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	13
Dann	Benign	0.84
DEOGEN2	Benign	0.034	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.075	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.13	N;.;.
REVEL	Benign	0.16
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.24
MVP		0.32
MPC		0.032
ClinPred		0.061	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.46

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

Other links and lift over

dbSNP: rs202177498; hg19: chr5-110428180; COSMIC: COSV72411063; COSMIC: COSV72411063;