1-193122201-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_024529.5(CDC73):c.2dup(p.Met1?) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.67

Genes affected

CDC73 (HGNC:16783): (cell division cycle 73) This gene encodes a tumor suppressor that is involved in transcriptional and post-transcriptional control pathways. The protein is a component of the the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A and with a histone methyltransferase complex. This protein appears to facilitate the association of 3' mRNA processing factors with actively-transcribed chromatin. Mutations in this gene have been linked to hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, and parathyroid carcinoma. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_024529.5 (CDC73) was described as [Pathogenic] in ClinVar as 3267
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-193122201-A-AT is Pathogenic according to our data. Variant chr1-193122201-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 2818838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC73	NM_024529.5	c.2dup	p.Met1?	frameshift_variant, start_lost	1/17	ENST00000367435.5
CDC73	XM_006711537.5	c.2dup	p.Met1?	frameshift_variant, start_lost	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC73	ENST00000367435.5	c.2dup	p.Met1?	frameshift_variant, start_lost	1/17	1	NM_024529.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parathyroid carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDC73 protein in which other variant(s) (p.Leu63Pro) have been determined to be pathogenic (PMID: 18755853; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with CDC73-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CDC73 mRNA. The next in-frame methionine is located at codon 177. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-193091331;