1-193122189-A-AG

Position:

• chr1-193122189-A-AG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 1.51

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 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: {Uncertain_significance=3, Likely_benign=2, Benign=6}.
• 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/exons	MANE	Protein	UniProt
CDC73	NM_024529.5	c.-4dupG		5_prime_UTR_variant	1/17	ENST00000367435.5	NP_078805.3
CDC73	XM_006711537.5	c.-4dupG		5_prime_UTR_variant	1/11		XP_006711600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435	c.-4dupG		5_prime_UTR_variant	1/17	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 940 AN: 151700 Hom.: 8 Cov.: 32

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.: 14 AF XY: 0.00745 AC XY: 993 AN XY: 133210

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.: 59 Cov.: 32 AF XY: 0.00883 AC XY: 6400 AN XY: 724476

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.: 8 Cov.: 32 AF XY: 0.00622 AC XY: 462 AN XY: 74226

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: 22 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2017	This variant is associated with the following publications: (PMID: 28774260) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CDC73: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Parathyroid carcinoma Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2016	- -

Isolated Hyperparathyroidism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hyperparathyroidism 2 with jaw tumors Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

CDC73-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2018

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

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: rs545666726; hg19: chr1-193091319;