5-111092387-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_139281.3(WDR36):c.-70C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,222 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: WDR36 NM_139281.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.86

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005258709).
• BP6: Variant 5-111092387-C-G is Benign according to our data. Variant chr5-111092387-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr5-111092387-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR36	NM_139281.3	c.-70C>G		5_prime_UTR_variant	1/23	ENST00000513710.4
WDR36	XM_047416729.1	c.-70C>G		5_prime_UTR_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR36	ENST00000513710.4	c.-70C>G		5_prime_UTR_variant	1/23	1	NM_139281.3	P1
WDR36	ENST00000505303.5	n.67C>G		non_coding_transcript_exon_variant	1/15	5
WDR36	ENST00000515784.1	n.41C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00374 AC: 939 AN: 251284 Hom.: 9 AF XY: 0.00400 AC XY: 544 AN XY: 135868

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00502 AC: 7344 AN: 1461870 Hom.: 28 Cov.: 31 AF XY: 0.00496 AC XY: 3605 AN XY: 727234

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00337 AC XY: 251 AN XY: 74496

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00472 Hom.: 3

Bravo AF: 0.00333

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00394 AC: 479

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	WDR36: BP4, BS1, BS2 -

Primary open angle glaucoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	2.0
Dann	Benign	0.49
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.090	N;.
REVEL	Uncertain	0.34
Polyphen		0.0	B;B
Vest4		0.66
MutPred		0.64		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.93
MPC		0.028
ClinPred		0.0059	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.056

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

LitVar

Other links and lift over

dbSNP: rs35629723; hg19: chr5-110428085;