chr17-41938634-C-CA

Position:

• chr17-41938634-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_031421.5(ODAD4):​c.704dupA​(p.His235fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ODAD4 NM_031421.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.11

Genes affected

ODAD4 (HGNC:25280): (outer dynein arm docking complex subunit 4) This gene encodes a tetratricopeptide repeat domain-containing protein that localizes to ciliary axonmenes and plays a role in the docking of the outer dynein arm to cilia. Mutations in this gene cause severely reduced ciliary motility and the disorder CILD35 (ciliary dyskinesia,primary, 35). Primary ciliary dyskinesia is often associated with recurrent respiratory infections, immotile spermatozoa, and situs inversus; an inversion in left-right body symmetry. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

ODAD4 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 17-41938634-C-CA is Pathogenic according to our data. Variant chr17-41938634-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2671845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD4	NM_031421.5	c.704dupA	p.His235fs	frameshift_variant	6/12	ENST00000377540.6	NP_113609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD4	ENST00000377540.6	c.704dupA	p.His235fs	frameshift_variant	6/12	1	NM_031421.5	ENSP00000478589.1
ODAD4	ENST00000591658.5	n.704dupA		non_coding_transcript_exon_variant	6/10	5		ENSP00000477931.1
ODAD4	ENST00000593239.5	n.*368dupA		non_coding_transcript_exon_variant	6/6	3		ENSP00000484975.1
ODAD4	ENST00000593239.5	n.*368dupA		3_prime_UTR_variant	6/6	3		ENSP00000484975.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Dec 11, 2023

The c.704dup variant leads to a frameshift (p.His235Glnfs*48) in ODAD4 (TTC25) gene, and is predicted to result in premature termination of translation. Bi-allelic loss-of-function variants in TTC25 are known as a genetic cause of primary ciliary dyskinesia (PMID:27486780). The patient was born to consanguineous parents and harbored the c.704dup in a homozygous state (the parents are heterozygous carriers). The c.704dup variant is absent in publicly available population and clinical databases (gnomAD, dbSNP, ClinVar). For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40094887;