rs759409470

Variant names:

• chr19-48297586-T-C
• rs759409470
• NM_001364171.2:c.1581+4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001364171.2(ODAD1):​c.1581+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,554,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ODAD1 NM_001364171.2 splice_region, intron
• Scores: Splicing: ADA: 0.9324
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD1	NM_001364171.2	c.1581+4A>G		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000674294.1	NP_001351100.1
ODAD1	NM_144577.4	c.1470+4A>G		splice_region_variant, intron_variant	Intron 13 of 13		NP_653178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ODAD1	ENST00000674294.1	c.1581+4A>G		splice_region_variant, intron_variant	Intron 15 of 15		NM_001364171.2	ENSP00000501363.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000107 AC: 2 AN: 186692 AF XY: 0.0000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 21 AN: 1402652 Hom.: 0 Cov.: 36 AF XY: 0.0000101 AC XY: 7 AN XY: 693110

African (AFR) AF: 0.00 AC: 0 AN: 31040

American (AMR) AF: 0.00 AC: 0 AN: 33744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39210

South Asian (SAS) AF: 0.00 AC: 0 AN: 76522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 0.0000157 AC: 17 AN: 1085868

Other (OTH) AF: 0.0000694 AC: 4 AN: 57666

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Feb 15, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects a highly conserved nucleotide within the consensus splice site of intron 13 The majority of introns (73%) have an A at this position (PMID: 9536098). This variant is present in population databases (rs759409470, ExAC 0.002%) but has not been reported in the literature in individuals with a CCDC114-related disease. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Benign	0.74
PhyloP100		2.0
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 4

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

Other links and lift over

dbSNP: rs759409470; hg19: chr19-48800843;