19-11422722-G-T

Position:

• chr19-11422722-G-T

Variant summary

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

The NM_145045.5(ODAD3):​c.1256C>A​(p.Ser419Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ODAD3 NM_145045.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.60

Genes affected

ODAD3 (HGNC:28303): (outer dynein arm docking complex subunit 3) This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

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 19-11422722-G-T is Pathogenic according to our data. Variant chr19-11422722-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 156366.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD3	NM_145045.5	c.1256C>A	p.Ser419Ter	stop_gained	9/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1	c.1094C>A	p.Ser365Ter	stop_gained	9/13		NP_001289382.1
ODAD3	NM_001302454.2	c.1076C>A	p.Ser359Ter	stop_gained	7/11		NP_001289383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9	c.1256C>A	p.Ser419Ter	stop_gained	9/13	1	NM_145045.5	ENSP00000348757	P2
ODAD3	ENST00000591179.5	c.1076C>A	p.Ser359Ter	stop_gained	7/11	1		ENSP00000466800	A2
ODAD3	ENST00000586836.5	c.683C>A	p.Ser228Ter	stop_gained	9/13	2		ENSP00000467429	A2
ODAD3	ENST00000591345.5	c.*1175C>A		3_prime_UTR_variant, NMD_transcript_variant	10/14	5		ENSP00000467313

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460244 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 30 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 14, 2023	This sequence change creates a premature translational stop signal (p.Ser419*) in the CCDC151 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC151 are known to be pathogenic (PMID: 25192045). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 25192045). ClinVar contains an entry for this variant (Variation ID: 156366). For these reasons, this variant has been classified as Pathogenic. -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.63	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.33
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587777780; hg19: chr19-11533390;