21-42850119-C-T

Position:

chr21-42850119-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018669.6(WDR4):c.1169G>A(p.Arg390Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,918 control chromosomes in the GnomAD database, including 30,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.24 ( 5538 hom., cov: 33)

Exomes 𝑓: 0.18 ( 24842 hom. )

Consequence

WDR4
NM_018669.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0760

Variant links:

Genes affected

WDR4 (HGNC:12756): (WD repeat domain 4) 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. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene is excluded as a candidate for a form of nonsyndromic deafness (DFNB10), but is still a candidate for other disorders mapped to 21q22.3 as well as for the development of Down syndrome phenotypes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

WDR4 links:

WDR4 (HGNC:):

WDR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3494492E-4).

BP6

Variant 21-42850119-C-T is Benign according to our data. Variant chr21-42850119-C-T is described in ClinVar as [Benign]. Clinvar id is 1234975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR4	NM_018669.6 linkuse as main transcript	c.1169G>A	p.Arg390Gln	missense_variant	11/11	ENST00000398208.3	NP_061139.2	P57081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WDR4	ENST00000398208.3 linkuse as main transcript	c.1169G>A	p.Arg390Gln	missense_variant	11/11	1	NM_018669.6	ENSP00000381266.2	P57081-1
WDR4	ENST00000330317.6 linkuse as main transcript	c.1169G>A	p.Arg390Gln	missense_variant	11/12	1		ENSP00000328671.2	P57081-1
WDR4	ENST00000476326.5 linkuse as main transcript	n.1084G>A		non_coding_transcript_exon_variant	11/11	1
WDR4	ENST00000492742.5 linkuse as main transcript	n.1312G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36517

AN:

152138

Hom.:

5536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.440

Gnomad AMI

AF:

0.168

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.232

GnomAD3 exomes

AF:

0.181

AC:

45447

AN:

251140

Hom.:

5000

AF XY:

0.181

AC XY:

24548

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.110

Gnomad SAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.171

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.177

AC:

258389

AN:

1461662

Hom.:

24842

Cov.:

AF XY:

0.178

AC XY:

129194

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.456

Gnomad4 AMR exome

AF:

0.133

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.116

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.170

Gnomad4 OTH exome

AF:

0.194

GnomAD4 genome

AF:

0.240

AC:

36547

AN:

152256

Hom.:

5538

Cov.:

AF XY:

0.234

AC XY:

17439

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.440

Gnomad4 AMR

AF:

0.169

Gnomad4 ASJ

AF:

0.196

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.200

Gnomad4 FIN

AF:

0.119

Gnomad4 NFE

AF:

0.170

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.192

Hom.:

5006

Bravo

AF:

0.253

TwinsUK

AF:

0.165

AC:

613

ALSPAC

AF:

0.174

AC:

670

ESP6500AA

AF:

0.436

AC:

1921

ESP6500EA

AF:

0.189

AC:

1626

ExAC

AF:

0.189

AC:

22890

Asia WGS

AF:

0.139

AC:

483

AN:

3478

EpiCase

AF:

0.184

EpiControl

AF:

0.178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephaly, growth deficiency, seizures, and brain malformations

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Galloway-Mowat syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.23

DANN

Benign

0.60

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.57

.;T

MetaRNN

Benign

0.00013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.83

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.023

Sift

Benign

0.69

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.012

B;B

Vest4

0.055

MPC

0.023

ClinPred

0.00058

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.011

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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