chr1-100499270-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033312.3(CDC14A):​c.1763C>A​(p.Ala588Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A588V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDC14A NM_033312.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060725898).

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>A		splice_region intron	N/A	NP_003663.2
	CDC14A	NM_033312.3		c.1763C>A	p.Ala588Glu	missense	Exon 15 of 15	NP_201569.1	Q9UNH5-2
	CDC14A	NM_001319211.2		c.1589C>A	p.Ala530Glu	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>A	p.Ala588Glu	missense	Exon 15 of 15	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000336454.5	TSL:1 MANE Select	c.1755+8C>A		splice_region intron	N/A	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000644676.1		c.1766C>A	p.Ala589Glu	missense	Exon 15 of 15	ENSP00000494661.1	A0A2R8YDJ8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251128 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000615

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: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.3
DANN	Benign	0.86
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.33
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.022
Sift	Uncertain	0.011	D
Sift4G	Benign	0.087	T
Polyphen		0.010	B
Vest4		0.11
MutPred		0.27		Gain of solvent accessibility (P = 9e-04)
MVP		0.14
MPC		0.17
ClinPred		0.65	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.23
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;