1-193142098-TGAGAGAGA-TGAGAGAGAGA

Variant names:

• chr1-193142098-T-TGA
• rs80356646
• NM_024529.5:c.729+50_729+51dupAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000367435.5(CDC73):​c.729+32_729+33insGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,434,650 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: CDC73 ENST00000367435.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.164
• 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 -10 ACMG points.

• BP6: Variant 1-193142098-T-TGA is Benign according to our data. Variant chr1-193142098-T-TGA is described in ClinVar as Likely_benign. ClinVar VariationId is 2692168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000638 (95/148800) while in subpopulation AMR AF = 0.00087 (13/14944). AF 95% confidence interval is 0.000636. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 95 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367435.5. 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+50_729+51dupAG		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+32_729+33insGA		intron	N/A	ENSP00000356405.4
	CDC73	ENST00000635846.1	TSL:5	c.729+32_729+33insGA		intron	N/A	ENSP00000490035.1
	CDC73	ENST00000643006.1		n.729+32_729+33insGA		intron	N/A	ENSP00000496633.1

Frequencies

GnomAD3 genomes AF: 0.000639 AC: 95 AN: 148720 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000871

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.000637

Gnomad FIN AF: 0.000307

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000553

Gnomad OTH AF: 0.000490

GnomAD2 exomes AF: 0.00110 AC: 116 AN: 105288 AF XY: 0.00111

Gnomad AFR exome AF: 0.00158

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000537

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.000765

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.000945 AC: 1215 AN: 1285850 Hom.: 1 Cov.: 0 AF XY: 0.000963 AC XY: 623 AN XY: 646642

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

African (AFR) AF: 0.000944 AC: 28 AN: 29654

American (AMR) AF: 0.000641 AC: 28 AN: 43670

Ashkenazi Jewish (ASJ) AF: 0.000365 AC: 9 AN: 24672

East Asian (EAS) AF: 0.000771 AC: 29 AN: 37604

South Asian (SAS) AF: 0.000467 AC: 38 AN: 81454

European-Finnish (FIN) AF: 0.000271 AC: 14 AN: 51610

Middle Eastern (MID) AF: 0.00148 AC: 8 AN: 5410

European-Non Finnish (NFE) AF: 0.00104 AC: 997 AN: 957498

Other (OTH) AF: 0.00118 AC: 64 AN: 54278

⚠️ 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: 0.000638 AC: 95 AN: 148800 Hom.: 0 Cov.: 32 AF XY: 0.000731 AC XY: 53 AN XY: 72522

African (AFR) AF: 0.000860 AC: 35 AN: 40684

American (AMR) AF: 0.000870 AC: 13 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5118

South Asian (SAS) AF: 0.000639 AC: 3 AN: 4698

European-Finnish (FIN) AF: 0.000307 AC: 3 AN: 9780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000553 AC: 37 AN: 66900

Other (OTH) AF: 0.000486 AC: 1 AN: 2058

Alfa AF: 0.000480 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356646; hg19: chr1-193111228;