10-1080454-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_014023.4(WDR37):c.374C>T(p.Thr125Ile) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T125A) has been classified 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:6 O:1
• 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-1080453-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1199795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 10-1080454-C-T is Pathogenic according to our data. Variant chr10-1080454-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-1080454-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR37	NM_014023.4	c.374C>T	p.Thr125Ile	missense_variant	5/14	ENST00000263150.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR37	ENST00000263150.9	c.374C>T	p.Thr125Ile	missense_variant	5/14	1	NM_014023.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurooculocardiogenitourinary syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 01, 2019	- -

Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

WDR37-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The WDR37 c.374C>T variant is predicted to result in the amino acid substitution p.Thr125Ile. This variant has been reported in the de novo state in multiple individuals with WDR37-related diseases (Reis et al. 2019. PubMed ID: 31327510; Kanca et al. 2019. PubMed ID: 31327508; Aldinger et al. 2019. PubMed ID: 31474318. Table S5; Zhu et al. 2022. PubMed ID: 35726512). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cerebellar vermis hypoplasia;C3278923:Ventriculomegaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Dobyns Lab, Seattle Children's Research Institute

Feb 18, 2019

- -

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

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;.;D;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;.;D;.;D;D
Sift4G	Uncertain	0.033	D;D;D;.;D;D
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.54
MutPred		0.31		Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);.;
MVP		0.27
MPC		1.7
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.69

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: rs1554823375; hg19: chr10-1126394;