rs552527338

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018076.5(ODAD2):c.1219G>A(p.Gly407Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ODAD2
NM_018076.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.550

Publications

0 publications found

Variant links:

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]

ODAD2 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 23
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ODAD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010136485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD2	NM_018076.5 link	c.1219G>A	p.Gly407Arg	missense_variant	Exon 9 of 20	ENST00000305242.10	NP_060546.2	Q5T2S8-1A0A140VKF7B7Z7Y0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ODAD2	ENST00000305242.10 link	c.1219G>A	p.Gly407Arg	missense_variant	Exon 9 of 20	1	NM_018076.5	ENSP00000306410.5		Q5T2S8-1

Frequencies

GnomAD3 genomes

AF:

0.000334

AC:

AN:

137882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00117

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:

0.0000466

Gnomad OTH

AF:

0.000561

GnomAD2 exomes

AF:

0.000101

AC:

AN:

79594

AF XY:

0.000101

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0000863

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000315

AC:

AN:

508490

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

270912

show subpopulations

African (AFR)

AF:

0.000374

AC:

AN:

13386

American (AMR)

AF:

0.0000437

AC:

AN:

22896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14522

East Asian (EAS)

AF:

0.00

AC:

AN:

31200

South Asian (SAS)

AF:

0.0000205

AC:

AN:

48798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2008

European-Non Finnish (NFE)

AF:

0.0000263

AC:

AN:

303622

Other (OTH)

AF:

0.0000360

AC:

AN:

27740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000333

AC:

AN:

137996

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

AN XY:

66506

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

36036

American (AMR)

AF:

0.00

AC:

AN:

13408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3280

East Asian (EAS)

AF:

0.00

AC:

AN:

4892

South Asian (SAS)

AF:

0.00

AC:

AN:

3866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000466

AC:

AN:

64334

Other (OTH)

AF:

0.000554

AC:

AN:

1806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000169

Hom.:

ExAC

AF:

0.0000997

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia 23

Uncertain:1

Sep 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ARMC4-related disease. ClinVar contains an entry for this variant (Variation ID: 412243). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces glycine with arginine at codon 407 of the ARMC4 protein (p.Gly407Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0029

T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.55

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.20

Sift

Benign

0.043

D;D

Sift4G

Benign

0.085

T;D

Polyphen

0.019

B;.

Vest4

0.23

MutPred

0.45

Loss of methylation at R408 (P = 0.0408);.;

MVP

0.44

MPC

1.9

ClinPred

0.012

GERP RS

3.0

Varity_R

0.062

gMVP

0.32

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over