rs1553291031

Variant names:

• chr1-193233075-C-G
• rs1553291031
• NM_024529.5:c.1237C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-193233075-C-G
• chr1-193233075-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024529.5(CDC73):​c.1237C>G​(p.Gln413Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. Q413P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.32
• 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), 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33278283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC73	NM_024529.5	c.1237C>G	p.Gln413Glu	missense_variant	Exon 14 of 17	ENST00000367435.5	NP_078805.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5	c.1237C>G	p.Gln413Glu	missense_variant	Exon 14 of 17	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parathyroid carcinoma Uncertain:1

Jul 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces glutamine with glutamic acid at codon 413 of the CDC73 protein (p.Gln413Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q413E variant (also known as c.1237C>G), located in coding exon 14 of the CDC73 gene, results from a C to G substitution at nucleotide position 1237. The glutamine at codon 413 is replaced by glutamic acid, an amino acid with highly 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	0.15
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;L;.
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.63	.;N;.
REVEL	Benign	0.15
Sift	Benign	0.036	.;D;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0090	B;B;.
Vest4		0.50
MutPred		0.43		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;
MVP		0.75
MPC		2.1
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.51
Mutation Taster		=63/37	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: rs1553291031; hg19: chr1-193202205;