3-167500155-T-C

Variant summary

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

The NM_001366157.1(WDR49):c.3029A>G(p.Lys1010Arg) variant causes a missense, splice region 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR49 NM_001366157.1 missense, splice_region
• Scores: Splicing: ADA: 0.0001531
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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=0.13749433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR49	NM_001366157.1	c.3029A>G	p.Lys1010Arg	missense_variant, splice_region_variant	18/19	ENST00000682715.1
WDR49	NM_001348951.2	c.2996A>G	p.Lys999Arg	missense_variant, splice_region_variant	18/19
WDR49	NM_001348952.2	c.2996A>G	p.Lys999Arg	missense_variant, splice_region_variant	18/19
WDR49	NM_001366158.1	c.1973A>G	p.Lys658Arg	missense_variant, splice_region_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR49	ENST00000682715.1	c.3029A>G	p.Lys1010Arg	missense_variant, splice_region_variant	18/19		NM_001366157.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Sep 14, 2022

The c.1973A>G (p.K658R) alteration is located in exon 14 (coding exon 13) of the WDR49 gene. This alteration results from a A to G substitution at nucleotide position 1973, causing the lysine (K) at amino acid position 658 to be replaced by an arginine (R). 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	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0022	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.57	N;.;.
REVEL	Benign	0.065
Sift	Benign	0.070	T;.;.
Sift4G	Uncertain	0.020	D;.;.
Polyphen		0.0	B;.;.
Vest4		0.074
MutPred		0.24		Loss of ubiquitination at K658 (P = 0.0141);.;.;
MVP		0.52
MPC		0.027
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.036
gMVP		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs1751503373; hg19: chr3-167217943;