rs28361212

Positions:

• chr1-100390824-A-C
• chr1-100390824-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003672.4(CDC14A):​c.309A>C​(p.Ala103Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,597,026 control chromosomes in the GnomAD database, including 4,021 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (2173 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (1848 hom.)
• Consequence: CDC14A NM_003672.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002205
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.80

Genes affected

CDC14A (HGNC:1718): (cell division cycle 14A) The protein encoded by this gene is a member of the dual specificity protein tyrosine phosphatase family. It is highly similar to Saccharomyces cerevisiae Cdc14, a protein tyrosine phosphatase involved in the exit of cell mitosis and initiation of DNA replication, suggesting a role in cell cycle control. This protein has been shown to interact with, and dephosphorylate tumor suppressor protein p53, and is thought to regulate the function of p53. Alternative splicing of this gene results in several transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

CDC14A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-100390824-A-C is Benign according to our data. Variant chr1-100390824-A-C is described in ClinVar as [Benign]. Clinvar id is 506035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC14A	NM_003672.4	c.309A>C	p.Ala103Ala	splice_region_variant, synonymous_variant	4/16	ENST00000336454.5	NP_003663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC14A	ENST00000336454.5	c.309A>C	p.Ala103Ala	splice_region_variant, synonymous_variant	4/16	1	NM_003672.4	ENSP00000336739.3

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13769 AN: 152100 Hom.: 2163 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0717

GnomAD3 exomes AF: 0.0237 AC: 5949 AN: 250778 Hom.: 893 AF XY: 0.0170 AC XY: 2306 AN XY: 135586

Gnomad AFR exome AF: 0.326

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00914 AC: 13212 AN: 1444808 Hom.: 1848 Cov.: 26 AF XY: 0.00786 AC XY: 5657 AN XY: 719828

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000413

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0908 AC: 13819 AN: 152218 Hom.: 2173 Cov.: 32 AF XY: 0.0875 AC XY: 6512 AN XY: 74428

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0164 Hom.: 731

Bravo AF: 0.102

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Ala103Ala in exon 4 of CDC14A: This variant is not expected to have clinical s ignificance because it has been identified in 32.67% (3374/10328) of African chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs28361212). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.081
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
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: rs28361212; hg19: chr1-100856380;