3-167522318-T-C

Position:

• chr3-167522318-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.2771A>G​(p.Tyr924Cys) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.745

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=0.11306465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR49	NM_001366157.1	c.2771A>G	p.Tyr924Cys	missense_variant	16/19	ENST00000682715.1
WDR49	NM_001348951.2	c.2738A>G	p.Tyr913Cys	missense_variant	16/19
WDR49	NM_001348952.2	c.2738A>G	p.Tyr913Cys	missense_variant	16/19
WDR49	NM_001366158.1	c.1715A>G	p.Tyr572Cys	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR49	ENST00000682715.1	c.2771A>G	p.Tyr924Cys	missense_variant	16/19		NM_001366157.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 20, 2024

The c.1715A>G (p.Y572C) alteration is located in exon 12 (coding exon 11) of the WDR49 gene. This alteration results from a A to G substitution at nucleotide position 1715, causing the tyrosine (Y) at amino acid position 572 to be replaced by a cysteine (C). 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	0.056
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.1
DANN	Benign	0.67
DEOGEN2	Benign	0.0037	T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Benign	0.042
Sift	Benign	0.044	D;.;.
Sift4G	Benign	0.064	T;.;.
Polyphen		0.96	D;.;.
Vest4		0.062
MutPred		0.24		Gain of glycosylation at S577 (P = 0.0092);.;.;
MVP		0.34
MPC		0.032
ClinPred		0.098	T
GERP RS		-2.6
Varity_R		0.093
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1319395008; hg19: chr3-167240106;