NM_018669.6:c.491A>C

Variant names:

• chr21-42862357-T-G
• rs1555976610
• NM_018669.6:c.491A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_018669.6(WDR4):​c.491A>C​(p.Asp164Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D164N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR4 NM_018669.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.77
• Publications: 1 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_018669.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 21-42862357-T-G is Pathogenic according to our data. Variant chr21-42862357-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 438741.Status of the report is no_assertion_criteria_provided, 0 stars.

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.491A>C	p.Asp164Ala	missense	Exon 5 of 11	NP_061139.2
	WDR4	NM_033661.5		c.491A>C	p.Asp164Ala	missense	Exon 5 of 12	NP_387510.1
	WDR4	NM_001260474.2		c.491A>C	p.Asp164Ala	missense	Exon 5 of 11	NP_001247403.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR4	ENST00000398208.3	TSL:1 MANE Select	c.491A>C	p.Asp164Ala	missense	Exon 5 of 11	ENSP00000381266.2
	WDR4	ENST00000330317.6	TSL:1	c.491A>C	p.Asp164Ala	missense	Exon 5 of 12	ENSP00000328671.2
	WDR4	ENST00000476326.5	TSL:1	n.406A>C		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Galloway-Mowat syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.84		Loss of ubiquitination at K168 (P = 0.0385)
MVP		0.50
MPC		0.20
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.81
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs1555976610; hg19: chr21-44282467;