chr1-193122202-T-A

Variant names:

• chr1-193122202-T-A
• NM_024529.5:c.2T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_024529.5(CDC73):​c.2T>A​(p.Met1?) variant causes a start lost change. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC73 NM_024529.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.67

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 42 pathogenic variants. Next in-frame start position is after 177 codons. Genomic position: 193141866. Lost 0.331 part of the original CDS.
• PS1: Another start lost variant in NM_024529.5 (CDC73) was described as [Pathogenic] in ClinVar as 3267
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC73	NM_024529.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 17	ENST00000367435.5	NP_078805.3
CDC73	XM_006711537.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 11		XP_006711600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 17	1	NM_024529.5	ENSP00000356405.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	.;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.96		Gain of ubiquitination at M1 (P = 0.0162);Gain of ubiquitination at M1 (P = 0.0162);Gain of ubiquitination at M1 (P = 0.0162);
MVP		0.90
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.98
gMVP		0.92

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: chr1-193091332;