rs80356643

Variant names:

• chr1-193122190-G-A
• rs80356643
• NM_024529.5:c.-11G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-193122190-G-A
• chr1-193122190-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_024529.5(CDC73):​c.-11G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,602,492 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: CDC73 NM_024529.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: 1.51
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hyperparathyroidism 2 with jaw tumors

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• hyperparathyroidism 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• parathyroid gland carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-193122190-G-A is Benign according to our data. Variant chr1-193122190-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21680.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000567 (85/150024) while in subpopulation AMR AF = 0.00332 (50/15060). AF 95% confidence interval is 0.00259. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 85 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024529.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	NM_024529.5	MANE Select	c.-11G>A		5_prime_UTR	Exon 1 of 17	NP_078805.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	ENST00000367435.5	TSL:1 MANE Select	c.-11G>A		5_prime_UTR	Exon 1 of 17	ENSP00000356405.4
	CDC73	ENST00000643006.1		n.-11G>A		non_coding_transcript_exon	Exon 1 of 18	ENSP00000496633.1
	CDC73	ENST00000643784.1		n.-11G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000494944.1

Frequencies

GnomAD3 genomes AF: 0.000567 AC: 85 AN: 149908 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000375

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000470 AC: 114 AN: 242478 AF XY: 0.000517

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000298 AC: 433 AN: 1452468 Hom.: 3 Cov.: 32 AF XY: 0.000314 AC XY: 227 AN XY: 722344

African (AFR) AF: 0.000212 AC: 7 AN: 33004

American (AMR) AF: 0.00169 AC: 75 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39384

South Asian (SAS) AF: 0.000326 AC: 28 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5730

European-Non Finnish (NFE) AF: 0.000233 AC: 257 AN: 1104932

Other (OTH) AF: 0.000834 AC: 50 AN: 59968

GnomAD4 genome AF: 0.000567 AC: 85 AN: 150024 Hom.: 1 Cov.: 32 AF XY: 0.000545 AC XY: 40 AN XY: 73384

African (AFR) AF: 0.000146 AC: 6 AN: 41102

American (AMR) AF: 0.00332 AC: 50 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000375 AC: 25 AN: 66692

Other (OTH) AF: 0.00144 AC: 3 AN: 2084

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperparathyroidism 2 with jaw tumors Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Parathyroid carcinoma Benign:1 Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Hyperparathyroidism 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperparathyroidism Benign:1

Aug 20, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4, BP6

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		1.5
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs80356643; hg19: chr1-193091320;