chr21-42850069-C-G

Variant names:

• chr21-42850069-C-G
• rs771861414
• NM_018669.6:c.1219G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018669.6(WDR4):​c.1219G>C​(p.Glu407Gln) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR4 NM_018669.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.755
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045929223).

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.1219G>C	p.Glu407Gln	missense	Exon 11 of 11	NP_061139.2
	WDR4	NM_033661.5		c.1219G>C	p.Glu407Gln	missense	Exon 11 of 12	NP_387510.1	P57081-1
	WDR4	NM_001260474.2		c.1216G>C	p.Glu406Gln	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.1219G>C	p.Glu407Gln	missense	Exon 11 of 11	ENSP00000381266.2	P57081-1
	WDR4	ENST00000330317.6	TSL:1	c.1219G>C	p.Glu407Gln	missense	Exon 11 of 12	ENSP00000328671.2	P57081-1
	WDR4	ENST00000476326.5	TSL:1	n.1134G>C		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.8
DANN	Benign	0.83
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.76
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.23	T
Sift4G	Benign	0.083	T
Polyphen		0.0020	B
Vest4		0.073
MutPred		0.077		Gain of MoRF binding (P = 0.0143)
MVP		0.25
MPC		0.022
ClinPred		0.048	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.25
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs771861414; hg19: chr21-44270179;