chr19-48303953-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_001364171.2(ODAD1):c.853G>A(p.Ala285Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,342 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A285A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

ODAD1
NM_001364171.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 1.78

Publications

10 publications found

Variant links:

Genes affected

ODAD1 (HGNC:26560): (outer dynein arm docking complex subunit 1) This gene encodes a coiled-coil domain-containing protein that is a component of the outer dynein arm docking complex in cilia cells. Mutations in this gene may cause primary ciliary dyskinesia 20. [provided by RefSeq, May 2013]

ODAD1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 20
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ODAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 19-48303953-C-T is Pathogenic according to our data. Variant chr19-48303953-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD1	NM_001364171.2 link	c.853G>A	p.Ala285Thr	missense_variant, splice_region_variant	Exon 9 of 16	ENST00000674294.1	NP_001351100.1
ODAD1	NM_144577.4 link	c.742G>A	p.Ala248Thr	missense_variant, splice_region_variant	Exon 7 of 14		NP_653178.3	Q96M63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ODAD1	ENST00000674294.1 link	c.853G>A	p.Ala285Thr	missense_variant, splice_region_variant	Exon 9 of 16		NM_001364171.2	ENSP00000501363.1		A0A6I8PTZ2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000243

AC:

AN:

250886

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000494

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000253

AC:

369

AN:

1461104

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

166

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000309

AC:

343

AN:

1111442

Other (OTH)

AF:

0.000199

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000312

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 27, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a common pathogenic variant among individuals of Dutch Volendam background (Onoufriadis et al., 2013; Kos et al., 2022); Non-canonical splice site variant demonstrated to result in loss of function (Onoufriadis et al., 2013); This variant is associated with the following publications: (PMID: 23261303, 20301301, 23261302, 35163670, 35343062) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 20

Pathogenic:4

Feb 16, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 10, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ODAD1 c.742G>A; p.Ala248Thr variant (rs147718607) is reported in the literature in several compound heterozygous and homozygous individuals and families affected with primary ciliary dyskinesia (Boaretto 2016, Knowles 2013, Kos 2022, Onoufriadis 2013). This variant is a known founder variant in the Dutch - Volendam population (Kos 2022, Onoufriadis 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 39637), and is found in the non-Finnish European population with an allele frequency of 0.05% (60/128,802 alleles) in the Genome Aggregation Database (v2.1.1). This missense variant disrupts the consensus donor splice site of exon 7, and RNA analysis of homozygous individuals showed the use of a cryptic splice site and introduction of a premature termination codon (Knowles 2013, Onoufriadis 2013). Based on available information, this variant is considered to be pathogenic. References: Boaretto F et al. Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients. J Mol Diagn. 2016 Nov;18(6):912-922. PMID: 27637300. Knowles MR et al. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):99-106. PMID: 23261302. Kos R et al. Primary ciliary dyskinesia in Volendam: Diagnostic and phenotypic features in patients with a CCDC114 mutation. Am J Med Genet C Semin Med Genet. 2022 Mar;190(1):89-101. PMID: 35343062. Onoufriadis A et al. Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):88-98. PMID: 23261303. -

Primary ciliary dyskinesia

Pathogenic:3

Dec 20, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.742G>A pathogenic mutation (also known as p.A248T), located in coding exon 6 of the CCDC114 gene, results from a G to A substitution at nucleotide position 742. The amino acid change results in alanine to threonine at codon 248, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This mutation was identified in muliple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous state (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98; Boaretto F et al. J Mol Diagn, 2016 Nov;18:912-922). In addition, analysis of RNA from affected individuals homozygous for this alteration showed an insertion of 79 nucleotides, resulting in premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 248 of the CCDC114 protein (p.Ala248Thr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs147718607, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23261302, 23261303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the use of a cryptic splice donor site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23261302). For these reasons, this variant has been classified as Pathogenic. -

Apr 02, 2019

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ODAD1-related disorder

Pathogenic:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ODAD1 c.742G>A variant is predicted to result in the amino acid substitution p.Ala248Thr. This variant has been reported to segregate in multiple families with primary ciliary dyskinesia and laterality defects in the Dutch Volendam population, and is believed to be a founder mutation (Onoufriadis et al. 2013. PubMed ID: 23261303; Knowles et al. 2013. PubMed ID: 23261302). The c.742G base is the terminal nucleotide of exon 7 and alterations of this base have been shown to disrupt the adjacent GT donor site, resulting in a frameshift and premature protein termination (Onoufriadis et al. 2013. PubMed ID: 23261303; Knowles et al. 2013. PubMed ID: 23261302). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Kartagener syndrome

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0020

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.095

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

REVEL

Benign

0.011

Sift

Benign

0.081

Sift4G

Benign

0.12

Polyphen

0.23

Vest4

0.21

MVP

0.16

MPC

0.29

ClinPred

0.42

GERP RS

2.3

Varity_R

0.032

gMVP

0.070

Mutation Taster

=29/71

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over