Genetic Variant CDC73:c.729+46_729+51delAGAGAG (chr1-193142098-TGAGAGA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_024529.5(CDC73):c.729+46_729+51delAGAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,437,786 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

CDC73
NM_024529.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Publications

4 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 Gene-Disease associations (from GenCC):

hyperparathyroidism 2 with jaw tumors
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
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

CDC73 links:

ENSG00000308280 (HGNC:):

ENSG00000308280 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000538 (8/148818) while in subpopulation AMR AF = 0.000134 (2/14946). AF 95% confidence interval is 0.0000288. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	NM_024529.5	MANE Select	c.729+46_729+51delAGAGAG		intron	N/A	NP_078805.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDC73	ENST00000367435.5	TSL:1 MANE Select	c.729+33_729+38delGAGAGA	intron	N/A	ENSP00000356405.4
CDC73	ENST00000958309.1		c.729+33_729+38delGAGAGA	intron	N/A	ENSP00000628368.1
CDC73	ENST00000958310.1		c.729+33_729+38delGAGAGA	intron	N/A	ENSP00000628369.1

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

148738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000747

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000570

AC:

AN:

105288

AF XY:

0.0000176

show subpopulations

Gnomad AFR exome

AF:

0.000143

Gnomad AMR exome

AF:

0.000144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000593

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000675

AC:

AN:

1288968

Hom.:

AF XY:

0.0000648

AC XY:

AN XY:

648086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29696

American (AMR)

AF:

0.0000458

AC:

AN:

43706

Ashkenazi Jewish (ASJ)

AF:

0.0000405

AC:

AN:

24710

East Asian (EAS)

AF:

0.00

AC:

AN:

37640

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.0000833

AC:

AN:

960240

Other (OTH)

AF:

0.0000552

AC:

AN:

54376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000538

AC:

AN:

148818

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72536

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40686

American (AMR)

AF:

0.000134

AC:

AN:

14946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

66904

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over