rs1553288361

Variant names:

• chr1-193212073-G-T
• rs1553288361
• NM_024529.5:c.1039G>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.1039G>T​(p.Ala347Ser) 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. A347V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC73 NM_024529.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56
• 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), Ambry Genetics, G2P, ClinGen
• 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

ENSG00000308280 (HGNC:):

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=0.3750068).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024529.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	NM_024529.5	MANE Select	c.1039G>T	p.Ala347Ser	missense	Exon 12 of 17	NP_078805.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	ENST00000367435.5	TSL:1 MANE Select	c.1039G>T	p.Ala347Ser	missense	Exon 12 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.1039G>T	p.Ala347Ser	missense	Exon 13 of 18	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.1036G>T	p.Ala346Ser	missense	Exon 12 of 17	ENSP00000628369.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432652 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 710314

African (AFR) AF: 0.00 AC: 0 AN: 32926

American (AMR) AF: 0.00 AC: 0 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.00 AC: 0 AN: 83260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092774

Other (OTH) AF: 0.00 AC: 0 AN: 59034

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parathyroid carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.17
Sift	Benign	0.28	T
Sift4G	Benign	0.40	T
Polyphen		0.41	B
Vest4		0.30
MutPred		0.32		Gain of glycosylation at A347 (P = 0.0078)
MVP		0.67
MPC		1.5
ClinPred		0.72	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.37
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553288361; hg19: chr1-193181203;