rs28361212

Variant names:

• chr1-100390824-A-C
• rs28361212
• NM_003672.4:c.309A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic deafness 105

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive nonsyndromic hearing loss 32

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia
• hearing impairment and infertile male syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003672.4. 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
	CDC14A	NM_003672.4	MANE Select	c.309A>C	p.Ala103Ala	splice_region synonymous	Exon 4 of 16	NP_003663.2
	CDC14A	NM_001319212.2		c.-483A>C		splice_region	Exon 4 of 14	NP_001306141.1
	CDC14A	NM_033312.3		c.309A>C	p.Ala103Ala	splice_region synonymous	Exon 4 of 15	NP_201569.1	Q9UNH5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC14A	ENST00000336454.5	TSL:1 MANE Select	c.309A>C	p.Ala103Ala	splice_region synonymous	Exon 4 of 16	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000361544.11	TSL:1	c.309A>C	p.Ala103Ala	splice_region synonymous	Exon 4 of 15	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000370124.8	TSL:1	c.309A>C	p.Ala103Ala	splice_region synonymous	Exon 4 of 11	ENSP00000359142.3	Q9UNH5-3

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

GnomAD2 exomes AF: 0.0237 AC: 5949 AN: 250778 AF XY: 0.0170

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 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

African (AFR) AF: 0.324 AC: 10654 AN: 32852

American (AMR) AF: 0.0157 AC: 702 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00106 AC: 91 AN: 85890

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53014

Middle Eastern (MID) AF: 0.0150 AC: 86 AN: 5734

European-Non Finnish (NFE) AF: 0.000413 AC: 453 AN: 1097226

Other (OTH) AF: 0.0199 AC: 1193 AN: 59844

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

African (AFR) AF: 0.318 AC: 13170 AN: 41458

American (AMR) AF: 0.0290 AC: 444 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68034

Other (OTH) AF: 0.0710 AC: 150 AN: 2114

Alfa AF: 0.0331 Hom.: 2104

Bravo AF: 0.102

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.081
DANN	Benign	0.51
PhyloP100		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28361212; hg19: chr1-100856380;