chr3-167522336-T-C

Position:

• chr3-167522336-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001366157.1(WDR49):​c.2753A>G​(p.Asn918Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,434,612 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0900

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06583354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR49	NM_001366157.1	c.2753A>G	p.Asn918Ser	missense_variant	16/19	ENST00000682715.1
WDR49	NM_001348951.2	c.2720A>G	p.Asn907Ser	missense_variant	16/19
WDR49	NM_001348952.2	c.2720A>G	p.Asn907Ser	missense_variant	16/19
WDR49	NM_001366158.1	c.1697A>G	p.Asn566Ser	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR49	ENST00000682715.1	c.2753A>G	p.Asn918Ser	missense_variant	16/19		NM_001366157.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1434612 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 713426

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

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

Aug 08, 2022

The c.1697A>G (p.N566S) 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 1697, causing the asparagine (N) at amino acid position 566 to be replaced by a serine (S). 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	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.29
DANN	Benign	0.35
DEOGEN2	Benign	0.0037	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.57	N;.;.
REVEL	Benign	0.0060
Sift	Benign	0.52	T;.;.
Sift4G	Benign	0.21	T;.;.
Polyphen		0.0080	B;.;.
Vest4		0.059
MutPred		0.21		Gain of glycosylation at S570 (P = 0.0222);.;.;
MVP		0.51
MPC		0.026
ClinPred		0.050	T
GERP RS		-0.68
Varity_R		0.020
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1752480664; hg19: chr3-167240124;