1-193125245-T-C

Variant names:

• chr1-193125245-T-C
• rs4466634
• NM_024529.5:c.237+28T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024529.5(CDC73):​c.237+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,232,496 control chromosomes in the GnomAD database, including 271,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30070 hom., cov: 32)
  • Exomes 𝑓: 0.67 (241893 hom.)
• Consequence: CDC73 NM_024529.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05
• Publications: 11 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

ENSG00000308280 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-193125245-T-C is Benign according to our data. Variant chr1-193125245-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC73	NM_024529.5	c.237+28T>C		intron_variant	Intron 2 of 16	ENST00000367435.5	NP_078805.3
CDC73	XM_006711537.5	c.237+28T>C		intron_variant	Intron 2 of 10		XP_006711600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5	c.237+28T>C		intron_variant	Intron 2 of 16	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94825 AN: 151906 Hom.: 30047 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.652 AC: 162428 AN: 249248 AF XY: 0.661

Gnomad AFR exome AF: 0.522

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.449

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.665 AC: 718584 AN: 1080472 Hom.: 241893 Cov.: 15 AF XY: 0.670 AC XY: 372092 AN XY: 555532

African (AFR) AF: 0.518 AC: 13458 AN: 25974

American (AMR) AF: 0.637 AC: 28151 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 16102 AN: 23842

East Asian (EAS) AF: 0.485 AC: 18350 AN: 37854

South Asian (SAS) AF: 0.763 AC: 59892 AN: 78528

European-Finnish (FIN) AF: 0.615 AC: 32667 AN: 53092

Middle Eastern (MID) AF: 0.727 AC: 3646 AN: 5012

European-Non Finnish (NFE) AF: 0.673 AC: 514461 AN: 763870

Other (OTH) AF: 0.662 AC: 31857 AN: 48108

GnomAD4 genome AF: 0.624 AC: 94888 AN: 152024 Hom.: 30070 Cov.: 32 AF XY: 0.626 AC XY: 46508 AN XY: 74316

African (AFR) AF: 0.521 AC: 21592 AN: 41410

American (AMR) AF: 0.674 AC: 10303 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2337 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2338 AN: 5178

South Asian (SAS) AF: 0.769 AC: 3709 AN: 4824

European-Finnish (FIN) AF: 0.617 AC: 6527 AN: 10574

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45829 AN: 67964

Other (OTH) AF: 0.654 AC: 1377 AN: 2104

Alfa AF: 0.601 Hom.: 8788

Bravo AF: 0.617

Asia WGS AF: 0.643 AC: 2235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperparathyroidism 2 with jaw tumors Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.6
DANN	Benign	0.49
PhyloP100		1.1
Mutation Taster		=5/95	disease causing

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: rs4466634; hg19: chr1-193094375;