rs1553191001

Variant names:

• chr1-100467953-C-G
• rs1553191001
• NM_003672.4:c.839-3C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_003672.4(CDC14A):​c.839-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CDC14A NM_003672.4 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.136
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-100467953-C-G is Pathogenic according to our data. Variant chr1-100467953-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559438.Status of the report is criteria_provided_single_submitter, 1 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.839-3C>G		splice_region intron	N/A	NP_003663.2
	CDC14A	NM_033312.3		c.839-3C>G		splice_region intron	N/A	NP_201569.1	Q9UNH5-2
	CDC14A	NM_001319210.2		c.839-3C>G		splice_region intron	N/A	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.839-3C>G		splice_region intron	N/A	ENSP00000336739.3	Q9UNH5-1
	CDC14A	ENST00000361544.11	TSL:1	c.839-3C>G		splice_region intron	N/A	ENSP00000354916.6	Q9UNH5-2
	CDC14A	ENST00000370124.8	TSL:1	c.839-3C>G		splice_region intron	N/A	ENSP00000359142.3	Q9UNH5-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432918 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712588

African (AFR) AF: 0.00 AC: 0 AN: 30960

American (AMR) AF: 0.00 AC: 0 AN: 36772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 38430

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102648

Other (OTH) AF: 0.00 AC: 0 AN: 59222

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 32 (1)
1	-	-	Monogenic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Benign	0.84
PhyloP100		0.14
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 1
DS_AL_spliceai		0.93		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1553191001;

hg19: chr1-100933509;