rs193025205

Variant names:

• chr1-193250724-C-A
• rs193025205
• NM_024529.5:c.*12C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-193250724-C-A
• chr1-193250724-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024529.5(CDC73):​c.*12C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,605,314 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (4 hom.)
• Consequence: CDC73 NM_024529.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.758
• Publications: 5 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), Ambry Genetics, G2P, ClinGen
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-193250724-C-A is Benign according to our data. Variant chr1-193250724-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221109.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 = 0.00187 (283/151742) while in subpopulation NFE AF = 0.00331 (224/67652). AF 95% confidence interval is 0.00295. There are 0 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 283 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	NM_024529.5	MANE Select	c.*12C>A		3_prime_UTR	Exon 17 of 17	NP_078805.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	ENST00000367435.5	TSL:1 MANE Select	c.*12C>A		3_prime_UTR	Exon 17 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.*12C>A		3_prime_UTR	Exon 18 of 18	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.*12C>A		3_prime_UTR	Exon 17 of 17	ENSP00000628369.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 283 AN: 151626 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00312

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00190 AC: 474 AN: 250010 AF XY: 0.00178

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00255 AC: 3711 AN: 1453572 Hom.: 4 Cov.: 28 AF XY: 0.00247 AC XY: 1788 AN XY: 723606

African (AFR) AF: 0.000421 AC: 14 AN: 33266

American (AMR) AF: 0.000157 AC: 7 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00274 AC: 146 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00309 AC: 3417 AN: 1105074

Other (OTH) AF: 0.00198 AC: 119 AN: 60106

GnomAD4 genome AF: 0.00187 AC: 283 AN: 151742 Hom.: 0 Cov.: 32 AF XY: 0.00170 AC XY: 126 AN XY: 74166

African (AFR) AF: 0.000409 AC: 17 AN: 41526

American (AMR) AF: 0.000263 AC: 4 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00312 AC: 33 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00331 AC: 224 AN: 67652

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Parathyroid carcinoma (2)
-	-	1	Hyperparathyroidism 1 (1)
-	-	1	Hyperparathyroidism 2 with jaw tumors (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.52
PhyloP100		0.76
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: rs193025205; hg19: chr1-193219854;