rs1553292974

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_024529.5(CDC73):​c.1558A>G​(p.Arg520Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,460,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R520R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CDC73
NM_024529.5 missense, splice_region

Scores

2
10
7
Splicing: ADA: 0.9796
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.11
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDC73NM_024529.5 linkc.1558A>G p.Arg520Gly missense_variant, splice_region_variant 16/17 ENST00000367435.5 NP_078805.3 Q6P1J9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDC73ENST00000367435.5 linkc.1558A>G p.Arg520Gly missense_variant, splice_region_variant 16/171 NM_024529.5 ENSP00000356405.4 Q6P1J9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000685
AC:
10
AN:
1460208
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726432
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Parathyroid carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 22, 2023In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 462753). 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 arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 520 of the CDC73 protein (p.Arg520Gly). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 14, 2023The p.R520G variant (also known as c.1558A>G), located in coding exon 16 of the CDC73 gene, results from an A to G substitution at nucleotide position 1558. The arginine at codon 520 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Uncertain
0.080
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D;D;T
Eigen
Benign
0.092
Eigen_PC
Benign
0.16
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
.;D;D
M_CAP
Benign
0.047
D
MetaRNN
Uncertain
0.55
D;D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.2
L;L;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-4.1
.;D;.
REVEL
Uncertain
0.35
Sift
Uncertain
0.018
.;D;.
Sift4G
Uncertain
0.039
.;D;.
Polyphen
0.43
B;B;.
Vest4
0.56
MutPred
0.56
Loss of MoRF binding (P = 0.0012);Loss of MoRF binding (P = 0.0012);.;
MVP
0.68
MPC
1.7
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.56
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.76
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553292974; hg19: chr1-193219000; API