rs11583414

Positions:

• chr1-193249713-C-G
• chr1-193249713-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000367435.5(CDC73):​c.1418-17C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0769 in 1,592,552 control chromosomes in the GnomAD database, including 5,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (364 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5024 hom.)
• Consequence: CDC73 ENST00000367435.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.170

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-193249713-C-G is Benign according to our data. Variant chr1-193249713-C-G is described in ClinVar as [Benign]. Clinvar id is 21682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC73	NM_024529.5	c.1418-17C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367435.5	NP_078805.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5	c.1418-17C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024529.5	ENSP00000356405	P1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8936 AN: 151634 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0771

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.0716

GnomAD3 exomes AF: 0.0592 AC: 14789 AN: 249960 Hom.: 593 AF XY: 0.0596 AC XY: 8055 AN XY: 135222

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0386

Gnomad ASJ exome AF: 0.0779

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.0600

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.0648

GnomAD4 exome AF: 0.0788 AC: 113566 AN: 1440802 Hom.: 5024 Cov.: 28 AF XY: 0.0776 AC XY: 55688 AN XY: 718040

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0397

Gnomad4 ASJ exome AF: 0.0792

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.0609

Gnomad4 NFE exome AF: 0.0914

Gnomad4 OTH exome AF: 0.0683

GnomAD4 genome AF: 0.0589 AC: 8936 AN: 151750 Hom.: 364 Cov.: 32 AF XY: 0.0568 AC XY: 4216 AN XY: 74178

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.0516

Gnomad4 ASJ AF: 0.0771

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0200

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.0901

Gnomad4 OTH AF: 0.0704

Alfa AF: 0.0481 Hom.: 59

Bravo AF: 0.0572

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: c.1418-17C>G in the CDC73 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 5.97%, including numerous 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 been reported as Benign/Polymorphism by a reputable database and published reports (Newey, 2010; Frank-Raue, 2011). Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Parathyroid carcinoma Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hyperparathyroidism 2 with jaw tumors Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.97
DANN	Benign	0.39

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: rs11583414; hg19: chr1-193218843;