chr1-193122106-G-A

Variant names:

• chr1-193122106-G-A
• rs143969598
• NM_024529.5:c.-95G>A

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.-95G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,211,200 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: CDC73 NM_024529.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.266
• Publications: 0 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=-0.52).
• BP6: Variant 1-193122106-G-A is Benign according to our data. Variant chr1-193122106-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294408.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 = 0.00129 (196/152298) while in subpopulation NFE AF = 0.00187 (127/68020). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 196 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.-95G>A		5_prime_UTR	Exon 1 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.-95G>A		5_prime_UTR	Exon 1 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.-95G>A		5_prime_UTR	Exon 2 of 18	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.-95G>A		5_prime_UTR	Exon 1 of 17	ENSP00000628369.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00171 AC: 1810 AN: 1058902 Hom.: 4 Cov.: 14 AF XY: 0.00161 AC XY: 871 AN XY: 539888

African (AFR) AF: 0.00106 AC: 27 AN: 25436

American (AMR) AF: 0.00219 AC: 85 AN: 38770

Ashkenazi Jewish (ASJ) AF: 0.000888 AC: 20 AN: 22524

East Asian (EAS) AF: 0.00 AC: 0 AN: 36404

South Asian (SAS) AF: 0.00 AC: 0 AN: 76058

European-Finnish (FIN) AF: 0.000142 AC: 7 AN: 49358

Middle Eastern (MID) AF: 0.000220 AC: 1 AN: 4546

European-Non Finnish (NFE) AF: 0.00211 AC: 1601 AN: 759120

Other (OTH) AF: 0.00148 AC: 69 AN: 46686

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74472

African (AFR) AF: 0.000842 AC: 35 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00157

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyperparathyroidism 2 with jaw tumors (2)
-	-	1	Hyperparathyroidism 1 (1)
-	-	1	Parathyroid carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		0.27
PromoterAI		-0.10	Neutral
Mutation Taster		=299/1	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: rs143969598; hg19: chr1-193091236;