NM_024529.5:c.-4dupG

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_024529.5(CDC73):c.-4dupG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00858 in 1,608,664 control chromosomes in the GnomAD database, including 67 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0062 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 59 hom. )

Consequence

CDC73
NM_024529.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 1.51

Variant links:

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]

CDC73 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 1-193122189-A-AG is Benign according to our data. Variant chr1-193122189-A-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286328.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0062 (942/151816) while in subpopulation NFE AF= 0.00939 (637/67872). AF 95% confidence interval is 0.00878. There are 8 homozygotes in gnomad4. There are 462 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 942 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC73	NM_024529.5 link	c.-4dupG		5_prime_UTR_variant	Exon 1 of 17	ENST00000367435.5	NP_078805.3	Q6P1J9
CDC73	XM_006711537.5 link	c.-4dupG		5_prime_UTR_variant	Exon 1 of 11		XP_006711600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435 link	c.-4dupG		5_prime_UTR_variant	Exon 1 of 17	1	NM_024529.5	ENSP00000356405.4		Q6P1J9

Frequencies

GnomAD3 genomes

AF:

0.00620

AC:

940

AN:

151700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00213

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00761

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00831

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00938

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00729

AC:

1785

AN:

244892

Hom.:

AF XY:

0.00745

AC XY:

993

AN XY:

133210

show subpopulations

Gnomad AFR exome

AF:

0.00276

Gnomad AMR exome

AF:

0.00545

Gnomad ASJ exome

AF:

0.00123

Gnomad EAS exome

AF:

0.00111

Gnomad SAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.00487

GnomAD4 exome

AF:

0.00883

AC:

12861

AN:

1456848

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

6400

AN XY:

724476

show subpopulations

Gnomad4 AFR exome

AF:

0.00192

Gnomad4 AMR exome

AF:

0.00500

Gnomad4 ASJ exome

AF:

0.000652

Gnomad4 EAS exome

AF:

0.000910

Gnomad4 SAS exome

AF:

0.0114

Gnomad4 FIN exome

AF:

0.00500

Gnomad4 NFE exome

AF:

0.00980

Gnomad4 OTH exome

AF:

0.00671

GnomAD4 genome

AF:

0.00620

AC:

942

AN:

151816

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

462

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00215

Gnomad4 AMR

AF:

0.00760

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.00853

Gnomad4 FIN

AF:

0.00293

Gnomad4 NFE

AF:

0.00939

Gnomad4 OTH

AF:

0.00617

Bravo

AF:

0.00631

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 28, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.-4dupG is located in the 5UTR region. Mutation taster predicts deleterious outcome. 4/5 in silico tools in Alamut predict no significant change on splicing pattern, however, these predictions should be taken with caution as Alamut tools are not meant to analyze UTR regions. The variant is present in the control population dataset of ExAC at frequency of 0.94%, predominantly in individuals of European descent (1.2%), including several homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0004%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals but cited as "Benign" by a clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28774260) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDC73: BP4, BS1, BS2 -

Parathyroid carcinoma

Uncertain:1Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated Hyperparathyroidism

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperparathyroidism 2 with jaw tumors

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDC73-related disorder

Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over