15-84643474-CG-C

Variant names:

• chr15-84643474-CG-C
• rs747109506
• NM_032856.5:c.1132delC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_032856.5(WDR73):​c.1132delC​(p.Arg378AlafsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,553,860 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: WDR73 NM_032856.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: -1.55

Genes affected

WDR73 (HGNC:25928): (WD repeat domain 73) The protein encoded by this gene is thought to contain multiple WD40 repeats. WD40 repeats are motifs that contain 40-60 amino acids, and usually end with Trp-Asp (WD). This protein is found in the cytoplasm during interphase, but accumulates at the spindle poles and astral microtubules during mitosis. Reduced expression of this gene results in abnormalities in the size and morphology of the nucleus. Mutations in this gene have been associated with Galloway-Mowat syndrome PMID: 25466283), which is a rare autosomal recessive disorder that affects both the central nervous system and kidneys. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ENSG00000291159 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0044 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00108 (1514/1401666) while in subpopulation NFE AF= 0.00133 (1437/1080444). AF 95% confidence interval is 0.00127. There are 2 homozygotes in gnomad4_exome. There are 716 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR73	NM_032856.5	c.1132delC	p.Arg378AlafsTer25	frameshift_variant	Exon 8 of 8	ENST00000434634.7	NP_116245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR73	ENST00000434634.7	c.1132delC	p.Arg378AlafsTer25	frameshift_variant	Exon 8 of 8	1	NM_032856.5	ENSP00000387982.3

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000613 AC: 98 AN: 159916 Hom.: 0 AF XY: 0.000614 AC XY: 52 AN XY: 84636

Gnomad AFR exome AF: 0.000116

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.00108 AC: 1514 AN: 1401666 Hom.: 2 Cov.: 33 AF XY: 0.00104 AC XY: 716 AN XY: 691668

Gnomad4 AFR exome AF: 0.0000942

Gnomad4 AMR exome AF: 0.000279

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000809

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74406

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000655 Hom.: 0

Bravo AF: 0.000672

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the WDR73 gene (p.Arg378Alafs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the WDR73 protein and extend the protein by 23 additional amino acid residues. This variant is present in population databases (rs775472894, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with WDR73-related conditions. ClinVar contains an entry for this variant (Variation ID: 286399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WDR73 c.1132delC (p.Arg378AlafsX25) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.001 in 1553860 control chromosomes in the gnomAD database, including 2 homozygotes. c.1132delC has been reported in the homozygous state in a consanguineous couple who had a deceased daughter, however, other pathogenic variants were also reported (IGHMPB2, DYNC2H1) and mimimal phenotype data was provided (Sallevelt_2021). This report does not provide unequivocal conclusions about association of the variant with Galloway-Mowat Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33742171). ClinVar contains an entry for this variant (Variation ID: 286399). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Galloway-Mowat syndrome 1 Uncertain:1

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs747109506; hg19: chr15-85186705;