10-1080436-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.356C>T(p.Ser119Phe) 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. S119Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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 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 chrnull-null-null-null is described in UniProt as null.
• PP5: Variant 10-1080436-C-T is Pathogenic according to our data. Variant chr10-1080436-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-1080436-C-T is described in Lovd as [Pathogenic]. Variant chr10-1080436-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR37	NM_014023.4	c.356C>T	p.Ser119Phe	missense_variant	5/14	ENST00000263150.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR37	ENST00000263150.9	c.356C>T	p.Ser119Phe	missense_variant	5/14	1	NM_014023.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurooculocardiogenitourinary syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 18, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -

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	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D;.;D;.;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.032	D;.;D;.;D;D
Sift4G	Uncertain	0.033	D;D;D;.;D;D
Polyphen		1.0	D;.;D;.;D;.
Vest4		0.66
MutPred		0.35		Loss of phosphorylation at S119 (P = 0.0277);Loss of phosphorylation at S119 (P = 0.0277);Loss of phosphorylation at S119 (P = 0.0277);Loss of phosphorylation at S119 (P = 0.0277);Loss of phosphorylation at S119 (P = 0.0277);.;
MVP		0.47
MPC		0.85
ClinPred		0.89	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.80

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: rs1589088690; hg19: chr10-1126376;