rs10494675

Positions:

• chr1-193181743-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000367435.5(CDC73):​c.973-22052T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 559,820 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.046 (159 hom., cov: 32)
  • Exomes 𝑓: 0.040 (364 hom.)
• Consequence: CDC73 ENST00000367435.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

Genes affected

B3GALT2 (HGNC:917): (beta-1,3-galactosyltransferase 2) This gene is a member of the beta-1,3-galactosyltransferase (beta3GalT) gene family. This family encodes type II membrane-bound glycoproteins with diverse enzymatic functions using different donor substrates (UDP-galactose and UDP-N-acetylglucosamine) and different acceptor sugars (N-acetylglucosamine, galactose, N-acetylgalactosamine). The beta3GalT genes are distantly related to the Drosophila Brainiac gene and have the protein coding sequence contained in a single exon. The beta3GalT proteins also contain conserved sequences not found in the beta4GalT or alpha3GalT proteins. The carbohydrate chains synthesized by these enzymes are designated as type 1, whereas beta4GalT enzymes synthesize type 2 carbohydrate chains. The ratio of type 1:type 2 chains changes during embryogenesis. By sequence similarity, the beta3GalT genes fall into at least two groups: beta3GalT4 and 4 other beta3GalT genes (beta3GalT1-3, beta3GalT5). This gene encodes a protein that functions in N-linked glycoprotein glycosylation and shows strict donor substrate specificity for UDP-galactose. [provided by RefSeq, Jul 2008]

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B3GALT2	NM_003783.3	c.-120-61A>G		intron_variant		ENST00000367434.5	NP_003774.1
CDC73	NM_024529.5	c.973-22052T>C		intron_variant		ENST00000367435.5	NP_078805.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B3GALT2	ENST00000367434.5	c.-120-61A>G		intron_variant		1	NM_003783.3	ENSP00000356404	P1
CDC73	ENST00000367435.5	c.973-22052T>C		intron_variant		1	NM_024529.5	ENSP00000356405	P1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6933 AN: 152160 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0489

GnomAD4 exome AF: 0.0398 AC: 16222 AN: 407542 Hom.: 364 AF XY: 0.0391 AC XY: 8237 AN XY: 210726

Gnomad4 AFR exome AF: 0.0574

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0485

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0430

GnomAD4 genome AF: 0.0456 AC: 6951 AN: 152278 Hom.: 159 Cov.: 32 AF XY: 0.0455 AC XY: 3388 AN XY: 74458

Gnomad4 AFR AF: 0.0581

Gnomad4 AMR AF: 0.0389

Gnomad4 ASJ AF: 0.0531

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0468 Hom.: 193

Bravo AF: 0.0464

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs10494675; hg19: chr1-193150873;