10-27812526-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018076.5(ODAD2):c.3121G>T(p.Ala1041Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,612,734 control chromosomes in the GnomAD database, including 2,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1041T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (226 hom., cov: 32)
  • Exomes 𝑓: 0.020 (2416 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.41

Genes affected

ODAD2 (HGNC:25583): (outer dynein arm docking complex subunit 2) The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017198324).
• BP6: Variant 10-27812526-C-A is Benign according to our data. Variant chr10-27812526-C-A is described in ClinVar as [Benign]. Clinvar id is 417179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD2	NM_018076.5	c.3121G>T	p.Ala1041Ser	missense_variant	20/20	ENST00000305242.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD2	ENST00000305242.10	c.3121G>T	p.Ala1041Ser	missense_variant	20/20	1	NM_018076.5	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3331 AN: 152062 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.0505 AC: 12610 AN: 249854 Hom.: 990 AF XY: 0.0495 AC XY: 6686 AN XY: 135064

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.221

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0199 AC: 29010 AN: 1460554 Hom.: 2416 Cov.: 30 AF XY: 0.0220 AC XY: 16017 AN XY: 726570

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.0356

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.0272

GnomAD4 genome AF: 0.0219 AC: 3339 AN: 152180 Hom.: 226 Cov.: 32 AF XY: 0.0262 AC XY: 1949 AN XY: 74406

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0616

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0117 Hom.: 262

Bravo AF: 0.0232

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0478 AC: 5798

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2016

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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Primary ciliary dyskinesia 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.0035	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.30
Sift	Benign	0.091	T
Sift4G	Benign	0.26	T
Polyphen		0.21	B
Vest4		0.15
MPC		0.25
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3737184; hg19: chr10-28101455; COSMIC: COSV59459467;