1-193212082-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024529.5(CDC73):c.1048C>T(p.Pro350Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. P350L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CDC73
NM_024529.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.02

Publications

1 publications found

Variant links:

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

CDC73 links:

ENSG00000308280 (HGNC:):

ENSG00000308280 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2228285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC73	NM_024529.5 link	c.1048C>T	p.Pro350Ser	missense_variant	Exon 12 of 17	ENST00000367435.5	NP_078805.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5 link	c.1048C>T	p.Pro350Ser	missense_variant	Exon 12 of 17	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32920

American (AMR)

AF:

0.00

AC:

AN:

42598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25606

East Asian (EAS)

AF:

0.00

AC:

AN:

39036

South Asian (SAS)

AF:

0.00

AC:

AN:

83288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092864

Other (OTH)

AF:

0.00

AC:

AN:

59064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Parathyroid carcinoma

Uncertain:1

Jun 21, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with serine at codon 350 of the CDC73 protein (p.Pro350Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CDC73-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P350S variant (also known as c.1048C>T), located in coding exon 12 of the CDC73 gene, results from a C to T substitution at nucleotide position 1048. The proline at codon 350 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

0.032

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.82

L;L;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.77

.;T;.

Sift4G

Benign

0.54

.;T;.

Polyphen

0.25

B;B;.

Vest4

0.31

MutPred

0.34

Loss of catalytic residue at P349 (P = 0.0116);Loss of catalytic residue at P349 (P = 0.0116);.;

MVP

0.50

MPC

1.2

ClinPred

0.80

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.45

Mutation Taster

=60/40

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over