NM_032856.5:c.129T>G

Variant names:

• chr15-84652783-A-C
• rs727502863
• NM_032856.5:c.129T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032856.5(WDR73):​c.129T>G​(p.Tyr43*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: WDR73 NM_032856.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.56
• Publications: 2 publications found

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]

WDR73 Gene-Disease associations (from GenCC):

• Galloway-Mowat syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• CAMOS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000291159 (HGNC:58684):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-84652783-A-C is Pathogenic according to our data. Variant chr15-84652783-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162610.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032856.5. 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
	WDR73	NM_032856.5	MANE Select	c.129T>G	p.Tyr43*	stop_gained	Exon 3 of 8	NP_116245.2	Q6P4I2
	WDR73	NR_130944.2		n.672T>G		non_coding_transcript_exon	Exon 2 of 7
	WDR73	NR_130945.2		n.138T>G		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR73	ENST00000434634.7	TSL:1 MANE Select	c.129T>G	p.Tyr43*	stop_gained	Exon 3 of 8	ENSP00000387982.3	Q6P4I2
	WDR73	ENST00000398528.7	TSL:1	n.205T>G		non_coding_transcript_exon	Exon 3 of 8
	WDR73	ENST00000948303.1		c.126T>G	p.Tyr42*	stop_gained	Exon 3 of 8	ENSP00000618362.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383716 Hom.: 0 Cov.: 28 AF XY: 0.00000147 AC XY: 1 AN XY: 681382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30930

American (AMR) AF: 0.00 AC: 0 AN: 32704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 35384

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071998

Other (OTH) AF: 0.00 AC: 0 AN: 57462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		1.6
Vest4		0.34
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=13/187	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727502863; hg19: chr15-85196014;