chr1-193142098-TGA-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000367435.5(CDC73):​c.729+33_729+34delGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 147,604 control chromosomes in the GnomAD database, including 27 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 32)
  • Exomes 𝑓: 0.17 (112 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC73 ENST00000367435.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 1-193142098-TGA-T is Benign according to our data. Variant chr1-193142098-TGA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2274/147604) while in subpopulation NFE AF = 0.0245 (1630/66416). AF 95% confidence interval is 0.0236. There are 27 homozygotes in GnomAd4. There are 1047 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2274 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+51delAG		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+34delGA		intron	N/A	ENSP00000356405.4
	CDC73	ENST00000635846.1	TSL:5	c.729+33_729+34delGA		intron	N/A	ENSP00000490035.1
	CDC73	ENST00000643006.1		n.729+33_729+34delGA		intron	N/A	ENSP00000496633.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2274 AN: 147540 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0929

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00176

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00340

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.00938

GnomAD2 exomes AF: 0.365 AC: 38410 AN: 105288 AF XY: 0.374

Gnomad AFR exome AF: 0.323

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.388

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.167 AC: 160078 AN: 958856 Hom.: 112 AF XY: 0.176 AC XY: 82555 AN XY: 469022

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

African (AFR) AF: 0.177 AC: 3600 AN: 20390

American (AMR) AF: 0.295 AC: 7031 AN: 23862

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 3418 AN: 13842

East Asian (EAS) AF: 0.249 AC: 5235 AN: 21036

South Asian (SAS) AF: 0.275 AC: 11957 AN: 43516

European-Finnish (FIN) AF: 0.230 AC: 6977 AN: 30376

Middle Eastern (MID) AF: 0.126 AC: 513 AN: 4058

European-Non Finnish (NFE) AF: 0.150 AC: 114242 AN: 763884

Other (OTH) AF: 0.188 AC: 7105 AN: 37892

⚠️ 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: 0.0154 AC: 2274 AN: 147604 Hom.: 27 Cov.: 32 AF XY: 0.0146 AC XY: 1047 AN XY: 71824

African (AFR) AF: 0.00419 AC: 170 AN: 40550

American (AMR) AF: 0.0106 AC: 157 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 6 AN: 3412

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.00341 AC: 16 AN: 4690

European-Finnish (FIN) AF: 0.0202 AC: 189 AN: 9374

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.0245 AC: 1630 AN: 66416

Other (OTH) AF: 0.00930 AC: 19 AN: 2044

Alfa AF: 0.156 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
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; COSMIC: COSV66466278; COSMIC: COSV66466278;