19-48303782-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001364171.2(ODAD1):c.856G>A(p.Gly286Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,606,834 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (6 hom.)
• Consequence: ODAD1 NM_001364171.2 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.916

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 Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-48303782-C-T is Benign according to our data. Variant chr19-48303782-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48303782-C-T is described in Lovd as [Benign]. Variant chr19-48303782-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00395 (602/152336) while in subpopulation AFR AF= 0.011 (459/41582). AF 95% confidence interval is 0.0102. There are 3 homozygotes in gnomad4. There are 278 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD1	NM_001364171.2	c.856G>A	p.Gly286Arg	missense_variant, splice_region_variant	10/16	ENST00000674294.1
ODAD1	NM_144577.4	c.745G>A	p.Gly249Arg	missense_variant, splice_region_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD1	ENST00000674294.1	c.856G>A	p.Gly286Arg	missense_variant, splice_region_variant	10/16		NM_001364171.2	P2
ODAD1	ENST00000315396.7	c.745G>A	p.Gly249Arg	missense_variant, splice_region_variant	8/14	1		A2
ODAD1	ENST00000474199.6	c.856G>A	p.Gly286Arg	missense_variant, splice_region_variant	10/15	2		A2
ODAD1	ENST00000674207.1	c.*564G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	8/13

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00170 AC: 413 AN: 243150 Hom.: 2 AF XY: 0.00143 AC XY: 188 AN XY: 131182

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000686

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000648

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.000840 AC: 1222 AN: 1454498 Hom.: 6 Cov.: 34 AF XY: 0.000809 AC XY: 585 AN XY: 723192

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.00767

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000823

Gnomad4 FIN exome AF: 0.0000942

Gnomad4 NFE exome AF: 0.000382

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00395 AC: 602 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00373 AC XY: 278 AN XY: 74500

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00285 Hom.: 0

Bravo AF: 0.00496

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.14
Dann	Benign	0.83
DEOGEN2	Benign	0.00014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.013
Sift	Benign	0.59	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.23		Gain of MoRF binding (P = 0.0381);
MVP		0.21
MPC		0.24
ClinPred		0.00069	T
GERP RS		-2.6
Varity_R		0.049
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs73942222; hg19: chr19-48807039; COSMIC: COSV99043758; COSMIC: COSV99043758;