chr1-193249850-G-C

Position:

• chr1-193249850-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_024529.5(CDC73):​c.1538G>C​(p.Arg513Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R513Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.98

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CDC73. . Gene score misZ 3.7315 (greater than the threshold 3.09). Trascript score misZ 3.3639 (greater than threshold 3.09). GenCC has associacion of gene with parathyroid gland carcinoma, familial isolated hyperparathyroidism, hyperparathyroidism 2 with jaw tumors, hyperparathyroidism 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC73	NM_024529.5	c.1538G>C	p.Arg513Pro	missense_variant	16/17	ENST00000367435.5	NP_078805.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5	c.1538G>C	p.Arg513Pro	missense_variant	16/17	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D;D;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	.;D;.
REVEL	Uncertain	0.42
Sift	Benign	0.14	.;T;.
Sift4G	Benign	0.19	.;T;.
Polyphen		0.62	P;P;.
Vest4		0.76
MutPred		0.71		Loss of MoRF binding (P = 0.001);Loss of MoRF binding (P = 0.001);.;
MVP		0.88
MPC		1.7
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-193218980;