19-984367-T-C

Variant names:

• chr19-984367-T-C
• rs1471359548
• NM_024100.4:c.14T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024100.4(WDR18):​c.14T>C​(p.Met5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,439,956 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WDR18 NM_024100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

WDR18 (HGNC:17956): (WD repeat domain 18) 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12470162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR18	NM_024100.4	c.14T>C	p.Met5Thr	missense_variant	Exon 1 of 10	ENST00000585809.6	NP_077005.2
WDR18	NM_001372085.1	c.14T>C	p.Met5Thr	missense_variant	Exon 3 of 12		NP_001359014.1
WDR18	NM_001372086.1	c.-117-101T>C		intron_variant	Intron 3 of 12		NP_001359015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR18	ENST00000585809.6	c.14T>C	p.Met5Thr	missense_variant	Exon 1 of 10	1	NM_024100.4	ENSP00000476117.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439956 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716136

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14T>C (p.M5T) alteration is located in exon 1 (coding exon 1) of the WDR18 gene. This alteration results from a T to C substitution at nucleotide position 14, causing the methionine (M) at amino acid position 5 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;.
Eigen	Benign	-0.013
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.26	B;.
Vest4		0.17
MutPred		0.25		Gain of glycosylation at M5 (P = 9e-04);Gain of glycosylation at M5 (P = 9e-04);
MVP		0.093
ClinPred		0.58	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.60
gMVP		0.74

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: rs1471359548; hg19: chr19-984367;