Variant chr3-49012203-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018031.6(WDR6):c.669G>C(p.Leu223Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

WDR6
NM_018031.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0740

Variant links:

Genes affected

WDR6 (HGNC:12758): (WD repeat domain 6) 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. The encoded protein interacts with serine/threonine kinase 11, and is implicated in cell growth arrest. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

WDR6 links:

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ACMG classification

Classification made for transcript

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=0.1118156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR6	NM_018031.6 link	c.669G>C	p.Leu223Phe	missense_variant	2/6	ENST00000608424.6	NP_060501.4	Q9NNW5A0A087X295Q9H9M3B3KRR8
WDR6	NM_001320546.3 link	c.591G>C	p.Leu197Phe	missense_variant	2/6		NP_001307475.1	Q9NNW5Q9H9M3
WDR6	NM_001320547.2 link	c.516G>C	p.Leu172Phe	missense_variant	2/6		NP_001307476.1	Q9NNW5E9PDU5B4E256Q9H9M3
WDR6	XM_047447371.1 link	c.669G>C	p.Leu223Phe	missense_variant	2/5		XP_047303327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR6	ENST00000608424.6 link	c.669G>C	p.Leu223Phe	missense_variant	2/6	1	NM_018031.6	ENSP00000477389.1		Q9NNW5

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251458

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000503

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.759G>C (p.L253F) alteration is located in exon 2 (coding exon 2) of the WDR6 gene. This alteration results from a G to C substitution at nucleotide position 759, causing the leucine (L) at amino acid position 253 to be replaced by a phenylalanine (F). 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

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;T;T;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.78

.;T;T;T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;.;.;L;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.2

N;.;N;.;N

REVEL

Benign

0.23

Sift

Benign

0.61

T;.;T;.;T

Sift4G

Benign

0.14

T;T;D;T;T

Polyphen

0.68, 0.84

.;.;.;P;P

Vest4

0.43

MutPred

0.57

.;.;.;Gain of glycosylation at S228 (P = 0.052);.;

MVP

0.38

MPC

0.43

ClinPred

0.43

GERP RS

0.19

Varity_R

0.034

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over