21-42850100-G-C

Variant names:

• chr21-42850100-G-C
• rs530886517
• NM_018669.6:c.1188C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_018669.6(WDR4):​c.1188C>G​(p.Pro396Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P396P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: WDR4 NM_018669.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.120
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-42850100-G-C is Benign according to our data. Variant chr21-42850100-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2911701.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000137 (20/1461694) while in subpopulation MID AF = 0.00156 (9/5764). AF 95% confidence interval is 0.000814. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.1188C>G	p.Pro396Pro	synonymous	Exon 11 of 11	NP_061139.2
	WDR4	NM_033661.5		c.1188C>G	p.Pro396Pro	synonymous	Exon 11 of 12	NP_387510.1	P57081-1
	WDR4	NM_001260474.2		c.1185C>G	p.Pro395Pro	synonymous	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.1188C>G	p.Pro396Pro	synonymous	Exon 11 of 11	ENSP00000381266.2	P57081-1
	WDR4	ENST00000330317.6	TSL:1	c.1188C>G	p.Pro396Pro	synonymous	Exon 11 of 12	ENSP00000328671.2	P57081-1
	WDR4	ENST00000476326.5	TSL:1	n.1103C>G		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251126 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461694 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727164

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111956

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.0
DANN	Benign	0.48
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs530886517; hg19: chr21-44270210;