rs770734388

chr1-193212401-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_024529.5(CDC73):c.1078C>T(p.Pro360Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000691 in 1,447,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P360L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CDC73
NM_024529.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP2

Missense variant where missense usually causes diseases, CDC73

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC73	NM_024529.5 linkuse as main transcript	c.1078C>T	p.Pro360Ser	missense_variant	13/17	ENST00000367435.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC73	ENST00000367435.5 linkuse as main transcript	c.1078C>T	p.Pro360Ser	missense_variant	13/17	1	NM_024529.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248960

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000691

AC:

AN:

1447418

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

720274

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000817

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Parathyroid carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 10, 2022

ClinVar contains an entry for this variant (Variation ID: 572624). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. This variant is present in population databases (rs770734388, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 360 of the CDC73 protein (p.Pro360Ser). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.1

M;M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.92

Polyphen

1.0

D;D;.

Vest4

0.98

MutPred

0.74

Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;

MVP

0.92

MPC

2.3

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over