Genetic Variant NM_024529.5:c.973-22052T>C (chr1-193181743-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024529.5(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
NM_024529.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.74

Publications

9 publications found

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]

CDC73 links:

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]

B3GALT2 links:

ENSG00000308280 (HGNC:):

ENSG00000308280 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDC73	NM_024529.5 link	c.973-22052T>C		intron_variant	Intron 10 of 16	ENST00000367435.5	NP_078805.3	Q6P1J9
B3GALT2	NM_003783.3 link	c.-120-61A>G		intron_variant	Intron 1 of 1	ENST00000367434.5	NP_003774.1	O43825

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5 link	c.973-22052T>C		intron_variant	Intron 10 of 16	1	NM_024529.5	ENSP00000356405.4		Q6P1J9
B3GALT2	ENST00000367434.5 link	c.-120-61A>G		intron_variant	Intron 1 of 1	1	NM_003783.3	ENSP00000356404.4		O43825

Frequencies

GnomAD3 genomes

AF:

0.0456

AC:

6933

AN:

152160

Hom.:

157

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.0574

AC:

604

AN:

10524

American (AMR)

AF:

0.0338

AC:

425

AN:

12556

Ashkenazi Jewish (ASJ)

AF:

0.0485

AC:

610

AN:

12590

East Asian (EAS)

AF:

0.000107

AC:

AN:

28126

South Asian (SAS)

AF:

0.0149

AC:

415

AN:

27832

European-Finnish (FIN)

AF:

0.0420

AC:

1469

AN:

34978

Middle Eastern (MID)

AF:

0.0486

AC:

AN:

1832

European-Non Finnish (NFE)

AF:

0.0454

AC:

11582

AN:

255272

Other (OTH)

AF:

0.0430

AC:

1025

AN:

23832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

771

1542

2313

3084

3855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0456

AC:

6951

AN:

152278

Hom.:

159

Cov.:

AF XY:

0.0455

AC XY:

3388

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0581

AC:

2414

AN:

41562

American (AMR)

AF:

0.0389

AC:

595

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0531

AC:

184

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0156

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0449

AC:

477

AN:

10616

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3077

AN:

68018

Other (OTH)

AF:

0.0479

AC:

101

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

343

686

1028

1371

1714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0467

Hom.:

253

Bravo

AF:

0.0464

Asia WGS

AF:

0.0140

AC:

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

(source)

DANN

Benign

0.68

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over