10-1080469-C-T

Position:

• chr10-1080469-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_014023.4(WDR37):​c.389C>T​(p.Thr130Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR37 NM_014023.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.76

Genes affected

WDR37 (HGNC:31406): (WD repeat domain 37) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-1080469-C-T is Pathogenic according to our data. Variant chr10-1080469-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-1080469-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR37	NM_014023.4	c.389C>T	p.Thr130Ile	missense_variant	5/14	ENST00000263150.9	NP_054742.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR37	ENST00000263150.9	c.389C>T	p.Thr130Ile	missense_variant	5/14	1	NM_014023.4	ENSP00000263150.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurooculocardiogenitourinary syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2022

The c.389C>T (p.T130I) alteration is located in exon 5 (coding exon 4) of the WDR37 gene. This alteration results from a C to T substitution at nucleotide position 389, causing the threonine (T) at amino acid position 130 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple patients with clinical features consistent with WDR37-related neurooculocardiogenitourinary syndrome (Kanca, 2019; Reis, 2019; Gubbels, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Congenital ocular coloboma;C0014544:Epilepsy;C0424605:Developmental delay;C1737329:Dysmorphism;C3714756:Intellectual disability;C5231391:Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

May 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;.;D;.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;.;D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;.;D;D
Polyphen		0.19	B;.;D;.;B;.
Vest4		0.53
MutPred		0.35		Gain of methylation at K127 (P = 0.0461);Gain of methylation at K127 (P = 0.0461);Gain of methylation at K127 (P = 0.0461);Gain of methylation at K127 (P = 0.0461);Gain of methylation at K127 (P = 0.0461);.;
MVP		0.23
MPC		0.72
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.63

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: rs1589088703; hg19: chr10-1126409;