rs147718607

chr19-48303953-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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. 13/23 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 (★★).

• 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:10 O:1
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 id is 39637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48303953-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD1	NM_001364171.2	c.853G>A	p.Ala285Thr	missense_variant, splice_region_variant	9/16	ENST00000674294.1
ODAD1	NM_144577.4	c.742G>A	p.Ala248Thr	missense_variant, splice_region_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD1	ENST00000674294.1	c.853G>A	p.Ala285Thr	missense_variant, splice_region_variant	9/16		NM_001364171.2	P2
ODAD1	ENST00000315396.7	c.742G>A	p.Ala248Thr	missense_variant, splice_region_variant	7/14	1		A2
ODAD1	ENST00000474199.6	c.853G>A	p.Ala285Thr	missense_variant, splice_region_variant	9/15	2		A2
ODAD1	ENST00000674207.1	c.*561G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	7/13

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152238 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 250886 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135576

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 SAS 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.: 1 Cov.: 33 AF XY: 0.000228 AC XY: 166 AN XY: 726716

Gnomad4 AFR exome AF: 0.0000299

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: 0.000243

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000371 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2022	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) -

Primary ciliary dyskinesia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	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 disrupted 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 introduces a premature termination codon (PMID: 23261302). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Apr 02, 2019	- -

Primary ciliary dyskinesia 20 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2013	- -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	22
Dann	Benign	0.93
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.011
Sift	Benign	0.081	T
Sift4G	Benign	0.12	T
Polyphen		0.23	B
Vest4		0.21
MVP		0.16
MPC		0.29
ClinPred		0.42	T
GERP RS		2.3
Varity_R		0.032
gMVP		0.070

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

LitVar

Other links and lift over

dbSNP: rs147718607; hg19: chr19-48807210;