10-1080453-A-G

Position:

• chr10-1080453-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The NM_014023.4(WDR37):​c.373A>G​(p.Thr125Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. T125I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR37 NM_014023.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.15

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-1080454-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 10-1080453-A-G is Pathogenic according to our data. 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36408308). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR37	NM_014023.4	c.373A>G	p.Thr125Ala	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.373A>G	p.Thr125Ala	missense_variant	5/14	1	NM_014023.4	ENSP00000263150.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2023

The c.373A>G (p.T125A) alteration is located in exon 5 (coding exon 4) of the WDR37 gene. This alteration results from a A to G substitution at nucleotide position 373, causing the threonine (T) at amino acid position 125 to be replaced by an alanine (A). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported as a de novo occurrence in an individual with WDR37-related neurooculocardiogenitourinary syndrome (DECIPHER v.9.32). 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 likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2024

De novo variant with confirmed parentage in a patient in published literature from a cohort of individuals with developmental disorders; however, detailed clinical information was not provided and de novo variants in other genes were reported (PMID: 33057194); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35982159, 33057194) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.030	T;.;T;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.42	N;.;N;.;N;N
REVEL	Benign	0.25
Sift	Benign	0.77	T;.;T;.;T;T
Sift4G	Benign	0.93	T;T;T;.;T;T
Polyphen		0.98	D;.;P;.;D;.
Vest4		0.47
MutPred		0.24		Loss of glycosylation at T125 (P = 0.0283);Loss of glycosylation at T125 (P = 0.0283);Loss of glycosylation at T125 (P = 0.0283);Loss of glycosylation at T125 (P = 0.0283);Loss of glycosylation at T125 (P = 0.0283);.;
MVP		0.28
MPC		1.6
ClinPred		0.83	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-1126393;