NM_024529.5:c.729+48_729+51delAGAG

Variant names:

• chr1-193142098-TGAGA-T
• rs80356646
• NM_024529.5:c.729+48_729+51delAGAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_024529.5(CDC73):​c.729+48_729+51delAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,415,542 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: CDC73 NM_024529.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 4 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000148 (22/148670) while in subpopulation SAS AF = 0.000212 (1/4708). AF 95% confidence interval is 0.000126. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 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.729+48_729+51delAGAG		intron	N/A	NP_078805.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	ENST00000367435.5	TSL:1 MANE Select	c.729+33_729+36delGAGA		intron	N/A	ENSP00000356405.4
	CDC73	ENST00000958309.1		c.729+33_729+36delGAGA		intron	N/A	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.729+33_729+36delGAGA		intron	N/A	ENSP00000628369.1

Frequencies

GnomAD3 genomes AF: 0.000148 AC: 22 AN: 148670 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000209

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00186 AC: 196 AN: 105288 AF XY: 0.00183

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00150 AC: 1905 AN: 1266872 Hom.: 0 AF XY: 0.00137 AC XY: 872 AN XY: 636814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00103 AC: 30 AN: 29218

American (AMR) AF: 0.000581 AC: 25 AN: 42998

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 21 AN: 24188

East Asian (EAS) AF: 0.000898 AC: 33 AN: 36750

South Asian (SAS) AF: 0.000773 AC: 62 AN: 80254

European-Finnish (FIN) AF: 0.000574 AC: 29 AN: 50500

Middle Eastern (MID) AF: 0.00168 AC: 9 AN: 5354

European-Non Finnish (NFE) AF: 0.00170 AC: 1606 AN: 944302

Other (OTH) AF: 0.00169 AC: 90 AN: 53308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000148 AC: 22 AN: 148670 Hom.: 0 Cov.: 32 AF XY: 0.000152 AC XY: 11 AN XY: 72406

African (AFR) AF: 0.000123 AC: 5 AN: 40582

American (AMR) AF: 0.000134 AC: 2 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000209 AC: 14 AN: 66888

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.00148 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	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: rs80356646; hg19: chr1-193111228;