21-42850103-CCC-ACG

Variant names:

• chr21-42850103-CCC-ACG
• NM_018669.6:c.1183_1185delGGGinsCGT
• WDR4 p.Gly395Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018669.6(WDR4):​c.1183_1185delGGGinsCGT​(p.Gly395Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR4 NM_018669.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.760
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1183_1185delGGGinsCGT	p.Gly395Arg	missense	N/A	NP_061139.2
	WDR4	NM_033661.5		c.1183_1185delGGGinsCGT	p.Gly395Arg	missense	N/A	NP_387510.1	P57081-1
	WDR4	NM_001260474.2		c.1180_1182delGGGinsCGT	p.Gly394Arg	missense	N/A	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.1183_1185delGGGinsCGT	p.Gly395Arg	missense	N/A	ENSP00000381266.2	P57081-1
	WDR4	ENST00000330317.6	TSL:1	c.1183_1185delGGGinsCGT	p.Gly395Arg	missense	N/A	ENSP00000328671.2	P57081-1
	WDR4	ENST00000476326.5	TSL:1	n.1098_1100delGGGinsCGT		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-44270213;