1-193212066-T-G

Variant names:

• chr1-193212066-T-G
• rs148612206
• NM_024529.5:c.1032T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024529.5(CDC73):​c.1032T>G​(p.Val344Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,583,232 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V344V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (11 hom.)
• Consequence: CDC73 NM_024529.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001305
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.47
• Publications: 3 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 1-193212066-T-G is Benign according to our data. Variant chr1-193212066-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000657 (100/152138) while in subpopulation NFE AF = 0.000235 (16/68028). AF 95% confidence interval is 0.000147. There are 2 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 100 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC73	NM_024529.5	MANE Select	c.1032T>G	p.Val344Val	splice_region synonymous	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.1032T>G	p.Val344Val	splice_region synonymous	Exon 12 of 17	ENSP00000356405.4	Q6P1J9
	CDC73	ENST00000958309.1		c.1032T>G	p.Val344Val	splice_region synonymous	Exon 13 of 18	ENSP00000628368.1
	CDC73	ENST00000958310.1		c.1029T>G	p.Val343Val	splice_region synonymous	Exon 12 of 17	ENSP00000628369.1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00116 AC: 246 AN: 211726 AF XY: 0.00124

Gnomad AFR exome AF: 0.0000758

Gnomad AMR exome AF: 0.0000628

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000558 AC: 799 AN: 1431094 Hom.: 11 Cov.: 28 AF XY: 0.000609 AC XY: 432 AN XY: 709508

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.0000472 AC: 2 AN: 42366

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 593 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.00 AC: 0 AN: 83116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.0000888 AC: 97 AN: 1091776

Other (OTH) AF: 0.00181 AC: 107 AN: 58962

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152138 Hom.: 2 Cov.: 32 AF XY: 0.000552 AC XY: 41 AN XY: 74332

African (AFR) AF: 0.0000483 AC: 2 AN: 41430

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.00191 AC: 4 AN: 2092

Alfa AF: 0.00132 Hom.: 4

Bravo AF: 0.000733

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Parathyroid carcinoma (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hyperparathyroidism 1 (1)
-	-	1	Hyperparathyroidism 2 with jaw tumors (1)
-	-	1	not specified (1)
-	-	1	Parathyroid carcinoma;C1704981:Hyperparathyroidism 2 with jaw tumors (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs148612206; hg19: chr1-193181196;