1-193233014-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_024529.5(CDC73):c.1176G>C(p.Lys392Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K392K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CDC73

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC73	NM_024529.5	c.1176G>C	p.Lys392Asn	missense_variant	14/17	ENST00000367435.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC73	ENST00000367435.5	c.1176G>C	p.Lys392Asn	missense_variant	14/17	1	NM_024529.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parathyroid carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDC73 protein function. ClinVar contains an entry for this variant (Variation ID: 531647). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 392 of the CDC73 protein (p.Lys392Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
Polyphen		1.0	D;D;.
Vest4		0.50
MutPred		0.47		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;
MVP		0.80
MPC		2.5
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.92
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs767993995; hg19: chr1-193202144;