chr1-193122058-G-C

Variant names:

• chr1-193122058-G-C
• rs778446879
• NM_024529.5:c.-143G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_024529.5(CDC73):​c.-143G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 751,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: CDC73 NM_024529.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.818
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/152194) while in subpopulation NFE AF = 0.000294 (20/68032). AF 95% confidence interval is 0.000194. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 36 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.-143G>C		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.-143G>C		5_prime_UTR	Exon 1 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.-143G>C		splice_region	Exon 2 of 18	ENSP00000628368.1
	CDC73	ENST00000958309.1		c.-143G>C		5_prime_UTR	Exon 2 of 18	ENSP00000628368.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000372 AC: 223 AN: 599172 Hom.: 0 Cov.: 8 AF XY: 0.000378 AC XY: 119 AN XY: 315202

African (AFR) AF: 0.0000611 AC: 1 AN: 16356

American (AMR) AF: 0.0000990 AC: 3 AN: 30290

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 80 AN: 16970

East Asian (EAS) AF: 0.00 AC: 0 AN: 31760

South Asian (SAS) AF: 0.0000175 AC: 1 AN: 57206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2678

European-Non Finnish (NFE) AF: 0.000324 AC: 121 AN: 373426

Other (OTH) AF: 0.000545 AC: 17 AN: 31174

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74344

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000280

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.78
PhyloP100		0.82
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs778446879; hg19: chr1-193091188;