17-41930838-G-C

Variant names:

• chr17-41930838-G-C
• rs886037888
• NM_031421.5:c.114+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_031421.5(ODAD4):​c.114+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ODAD4 NM_031421.5 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.80
• Publications: 0 publications found

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]

ODAD4 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 35

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD4	NM_031421.5	MANE Select	c.114+1G>C		splice_donor intron	N/A	NP_113609.1
	ODAD4	NM_001350319.2		c.114+1G>C		splice_donor intron	N/A	NP_001337248.1
	ODAD4	NR_110662.3		n.221+1G>C		splice_donor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD4	ENST00000377540.6	TSL:1 MANE Select	c.114+1G>C		splice_donor intron	N/A	ENSP00000478589.1
	ODAD4	ENST00000591658.5	TSL:5	n.114+1G>C		splice_donor intron	N/A	ENSP00000477931.1
	ODAD4	ENST00000593239.5	TSL:3	n.114+1G>C		splice_donor intron	N/A	ENSP00000484975.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1362176 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 676686

African (AFR) AF: 0.00 AC: 0 AN: 31234

American (AMR) AF: 0.00 AC: 0 AN: 38340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24128

East Asian (EAS) AF: 0.00 AC: 0 AN: 35438

South Asian (SAS) AF: 0.00 AC: 0 AN: 80902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1042300

Other (OTH) AF: 0.00 AC: 0 AN: 55910

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		6.8
GERP RS		5.7
PromoterAI		-0.42	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs886037888; hg19: chr17-40087091;