rs876661408

Variant names:

• chr1-100484440-C-T
• rs876661408
• NM_003672.4:c.1126C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003672.4(CDC14A):​c.1126C>T​(p.Arg376*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000555 in 1,442,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R376R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDC14A NM_003672.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.17
• Publications: 4 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)
• hearing impairment and infertile male syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 32

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000228086 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-100484440-C-T is Pathogenic according to our data. Variant chr1-100484440-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 235145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1126C>T	p.Arg376*	stop_gained	Exon 11 of 16	NP_003663.2
	CDC14A	NM_033312.3		c.1126C>T	p.Arg376*	stop_gained	Exon 11 of 15	NP_201569.1	Q9UNH5-2
	CDC14A	NM_001319210.2		c.1126C>T	p.Arg376*	stop_gained	Exon 11 of 17	NP_001306139.1	Q9UNH5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC14A	ENST00000336454.5	TSL:1 MANE Select	c.1126C>T	p.Arg376*	stop_gained	Exon 11 of 16	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000361544.11	TSL:1	c.1126C>T	p.Arg376*	stop_gained	Exon 11 of 15	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000370124.8	TSL:1	c.1126C>T	p.Arg376*	stop_gained	Exon 11 of 11	ENSP00000359142.3	Q9UNH5-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000431 AC: 1 AN: 231838 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.00000555 AC: 8 AN: 1442196 Hom.: 0 Cov.: 31 AF XY: 0.00000558 AC XY: 4 AN XY: 717172

African (AFR) AF: 0.00 AC: 0 AN: 32158

American (AMR) AF: 0.00 AC: 0 AN: 40394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 39006

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5522

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105126

Other (OTH) AF: 0.00 AC: 0 AN: 59542

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive nonsyndromic hearing loss 32 (2)
1	-	-	CDC14A-related disorder (1)
1	-	-	Ear malformation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.50	D
PhyloP100		1.2
Vest4		0.89
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs876661408; hg19: chr1-100949996;