rs1060500010

Variant names:

• chr1-193212398-A-G
• rs1060500010
• NM_024529.5:c.1075A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024529.5(CDC73):​c.1075A>G​(p.Thr359Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,444,388 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T359I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CDC73 NM_024529.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.42
• Publications: 3 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

ENSG00000308280 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1075A>G	p.Thr359Ala	missense	Exon 13 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.1075A>G	p.Thr359Ala	missense	Exon 13 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.1075A>G	p.Thr359Ala	missense	Exon 14 of 18	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.1072A>G	p.Thr358Ala	missense	Exon 13 of 17	ENSP00000628369.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444388 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 718660

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

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 43890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 82994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1100788

Other (OTH) AF: 0.00 AC: 0 AN: 59698

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00160812), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Parathyroid carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.74	P
Vest4		0.84
MutPred		0.49		Loss of phosphorylation at T359 (P = 0.0355)
MVP		0.61
MPC		2.0
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.72
Mutation Taster		=39/61	disease causing

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: rs1060500010; hg19: chr1-193181528;