chr21-42850119-C-T

Variant names:

• chr21-42850119-C-T
• rs6586250
• NM_018669.6:c.1169G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (5538 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24842 hom.)
• Consequence: WDR4 NM_018669.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0760
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly, growth deficiency, seizures, and brain malformations

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Galloway-Mowat syndrome 6

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018669.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR4	NM_018669.6	MANE Select	c.1169G>A	p.Arg390Gln	missense	Exon 11 of 11	NP_061139.2
	WDR4	NM_033661.5		c.1169G>A	p.Arg390Gln	missense	Exon 11 of 12	NP_387510.1	P57081-1
	WDR4	NM_001260474.2		c.1166G>A	p.Arg389Gln	missense	Exon 11 of 11	NP_001247403.1	P57081-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR4	ENST00000398208.3	TSL:1 MANE Select	c.1169G>A	p.Arg390Gln	missense	Exon 11 of 11	ENSP00000381266.2	P57081-1
	WDR4	ENST00000330317.6	TSL:1	c.1169G>A	p.Arg390Gln	missense	Exon 11 of 12	ENSP00000328671.2	P57081-1
	WDR4	ENST00000476326.5	TSL:1	n.1084G>A		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36517 AN: 152138 Hom.: 5536 Cov.: 33

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

GnomAD2 exomes AF: 0.181 AC: 45447 AN: 251140 AF XY: 0.181

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 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.: 32 AF XY: 0.178 AC XY: 129194 AN XY: 727134

African (AFR) AF: 0.456 AC: 15263 AN: 33470

American (AMR) AF: 0.133 AC: 5949 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5102 AN: 26130

East Asian (EAS) AF: 0.116 AC: 4616 AN: 39690

South Asian (SAS) AF: 0.208 AC: 17935 AN: 86238

European-Finnish (FIN) AF: 0.125 AC: 6671 AN: 53350

Middle Eastern (MID) AF: 0.281 AC: 1620 AN: 5764

European-Non Finnish (NFE) AF: 0.170 AC: 189541 AN: 1111942

Other (OTH) AF: 0.194 AC: 11692 AN: 60388

GnomAD4 genome AF: 0.240 AC: 36547 AN: 152256 Hom.: 5538 Cov.: 33 AF XY: 0.234 AC XY: 17439 AN XY: 74448

African (AFR) AF: 0.440 AC: 18256 AN: 41518

American (AMR) AF: 0.169 AC: 2579 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 682 AN: 3472

East Asian (EAS) AF: 0.101 AC: 523 AN: 5190

South Asian (SAS) AF: 0.200 AC: 967 AN: 4824

European-Finnish (FIN) AF: 0.119 AC: 1268 AN: 10620

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11539 AN: 68014

Other (OTH) AF: 0.229 AC: 485 AN: 2114

Alfa AF: 0.195 Hom.: 7914

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Galloway-Mowat syndrome 6 (1)
-	-	1	Microcephaly, growth deficiency, seizures, and brain malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.23
DANN	Benign	0.60
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		-0.076
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.023
Sift	Benign	0.69	T
Sift4G	Benign	0.80	T
Polyphen		0.012	B
Vest4		0.055
MPC		0.023
ClinPred		0.00058	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.011
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6586250; hg19: chr21-44270229; COSMIC: COSV57733674; COSMIC: COSV57733674;