chr1-100499270-C-T

Variant names:

• chr1-100499270-C-T
• rs139956023
• ENST00000361544.11:c.1763C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033312.3(CDC14A):​c.1763C>T​(p.Ala588Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,614,204 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: CDC14A NM_033312.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.332
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042932034).
• BP6: Variant 1-100499270-C-T is Benign according to our data. Variant chr1-100499270-C-T is described in ClinVar as Benign. ClinVar VariationId is 517536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00416 (633/152316) while in subpopulation AFR AF = 0.0141 (588/41568). AF 95% confidence interval is 0.0132. There are 3 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033312.3. 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.1755+8C>T		splice_region intron	N/A	NP_003663.2
	CDC14A	NM_033312.3		c.1763C>T	p.Ala588Val	missense	Exon 15 of 15	NP_201569.1	Q9UNH5-2
	CDC14A	NM_001319211.2		c.1589C>T	p.Ala530Val	missense	Exon 15 of 15	NP_001306140.1	A0A0U1RQX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC14A	ENST00000361544.11	TSL:1	c.1763C>T	p.Ala588Val	missense	Exon 15 of 15	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000336454.5	TSL:1 MANE Select	c.1755+8C>T		splice_region intron	N/A	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000644676.1		c.1766C>T	p.Ala589Val	missense	Exon 15 of 15	ENSP00000494661.1	A0A2R8YDJ8

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152198 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251128 AF XY: 0.000796

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000430 AC: 628 AN: 1461888 Hom.: 5 Cov.: 32 AF XY: 0.000380 AC XY: 276 AN XY: 727244

African (AFR) AF: 0.0142 AC: 477 AN: 33480

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1112006

Other (OTH) AF: 0.000993 AC: 60 AN: 60396

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74488

African (AFR) AF: 0.0141 AC: 588 AN: 41568

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00138 Hom.: 1

Bravo AF: 0.00481

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.7
DANN	Uncertain	0.98
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.33
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.040
Sift	Uncertain	0.022	D
Sift4G	Benign	1.0	T
Polyphen		0.021	B
Vest4		0.097
MVP		0.081
MPC		0.15
ClinPred		0.0083	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.20
Mutation Taster		=97/3	polymorphism

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: rs139956023; hg19: chr1-100964826; COSMIC: COSV100326279;