rs80356649

chr1-193142016-A-AAG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024529.5(CDC73):c.679_680insAG(p.Arg227LysfsTer31) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:3 O:1
• Conservation: PhyloP100: 9.69

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 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 1-193142016-A-AAG is Pathogenic according to our data. Variant chr1-193142016-A-AAG is described in ClinVar as [Pathogenic]. Clinvar id is 3270.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC73	NM_024529.5	c.679_680insAG	p.Arg227LysfsTer31	frameshift_variant	7/17	ENST00000367435.5
CDC73	XM_006711537.5	c.679_680insAG	p.Arg227LysfsTer31	frameshift_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC73	ENST00000367435.5	c.679_680insAG	p.Arg227LysfsTer31	frameshift_variant	7/17	1	NM_024529.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Parathyroid carcinoma Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

Hyperparathyroidism 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Hyperparathyroidism 2 with jaw tumors Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356649; hg19: chr1-193111146;