3-167500192-C-G

Variant summary

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

The NM_001366157.1(WDR49):c.2992G>C(p.Glu998Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. E998K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.17

Genes affected

WDR49 (HGNC:26587): (WD repeat domain 49) This gene encodes a member of the WD repeat protein family with nine WD repeats. 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

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=0.088041425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR49	NM_001366157.1	c.2992G>C	p.Glu998Gln	missense_variant	18/19	ENST00000682715.1
WDR49	NM_001348951.2	c.2959G>C	p.Glu987Gln	missense_variant	18/19
WDR49	NM_001348952.2	c.2959G>C	p.Glu987Gln	missense_variant	18/19
WDR49	NM_001366158.1	c.1936G>C	p.Glu646Gln	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR49	ENST00000682715.1	c.2992G>C	p.Glu998Gln	missense_variant	18/19		NM_001366157.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.1936G>C (p.E646Q) alteration is located in exon 14 (coding exon 13) of the WDR49 gene. This alteration results from a G to C substitution at nucleotide position 1936, causing the glutamic acid (E) at amino acid position 646 to be replaced by a glutamine (Q). 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	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.30
Dann	Benign	0.88
DEOGEN2	Benign	0.00048	T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.35	N;.;.
REVEL	Benign	0.031
Sift	Benign	0.37	T;.;.
Sift4G	Benign	0.20	T;.;.
Polyphen		0.0010	B;.;.
Vest4		0.059
MutPred		0.16		Loss of glycosylation at P643 (P = 0.0243);.;.;
MVP		0.62
MPC		0.029
ClinPred		0.070	T
GERP RS		3.2
Varity_R		0.046
gMVP		0.032

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: chr3-167217980; COSMIC: COSV57703996;