17-41936500-A-AT

Position:

• chr17-41936500-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_031421.5(ODAD4):​c.425_426insT​(p.Lys142AsnfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ODAD4 NM_031421.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 17-41936500-A-AT is Pathogenic according to our data. Variant chr17-41936500-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 254128.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD4	NM_031421.5	c.425_426insT	p.Lys142AsnfsTer12	frameshift_variant	4/12	ENST00000377540.6	NP_113609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD4	ENST00000377540.6	c.425_426insT	p.Lys142AsnfsTer12	frameshift_variant	4/12	1	NM_031421.5	ENSP00000478589	P1
ODAD4	ENST00000585530.1	c.*89_*90insT		3_prime_UTR_variant, NMD_transcript_variant	3/4	3		ENSP00000479460
ODAD4	ENST00000591658.5	c.425_426insT	p.Lys142AsnfsTer12	frameshift_variant, NMD_transcript_variant	4/10	5		ENSP00000477931
ODAD4	ENST00000593239.5	c.*89_*90insT		3_prime_UTR_variant, NMD_transcript_variant	4/6	3		ENSP00000484975

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary ciliary dyskinesia 35 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037889; hg19: chr17-40092753;