19-11426959-T-C

Position:

chr19-11426959-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_145045.5(ODAD3):c.526A>G(p.Arg176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,608,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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: 31)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

ODAD3
NM_145045.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.0800

Variant links:

Genes affected

ODAD3 (HGNC:28303): (outer dynein arm docking complex subunit 3) This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ODAD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03640431).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000328 (50/152310) while in subpopulation AMR AF= 0.00072 (11/15286). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ODAD3	NM_145045.5 linkuse as main transcript	c.526A>G	p.Arg176Gly	missense_variant	4/13	ENST00000356392.9
ODAD3	NM_001302453.1 linkuse as main transcript	c.364A>G	p.Arg122Gly	missense_variant	4/13
ODAD3	NM_001302454.2 linkuse as main transcript	c.448A>G	p.Arg150Gly	missense_variant	3/11
ODAD3	XM_017026241.2 linkuse as main transcript	c.526A>G	p.Arg176Gly	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD3	ENST00000356392.9 linkuse as main transcript	c.526A>G	p.Arg176Gly	missense_variant	4/13	1	NM_145045.5	P2	A5D8V7-1
ODAD3	ENST00000591179.5 linkuse as main transcript	c.448A>G	p.Arg150Gly	missense_variant	3/11	1		A2
ODAD3	ENST00000586836.5 linkuse as main transcript	c.-48A>G		5_prime_UTR_variant	4/13	2		A2
ODAD3	ENST00000591345.5 linkuse as main transcript	c.*445A>G		3_prime_UTR_variant, NMD_transcript_variant	5/14	5

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000334

AC:

AN:

242558

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

132578

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.000640

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.000506

GnomAD4 exome

AF:

0.000350

AC:

510

AN:

1456568

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

254

AN XY:

724880

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000356

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000328

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000452

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.000215

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 30

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 176 of the CCDC151 protein (p.Arg176Gly). This variant is present in population databases (rs143287033, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with CCDC151-related conditions. ClinVar contains an entry for this variant (Variation ID: 477984). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.526A>G (p.R176G) alteration is located in exon 4 (coding exon 4) of the CCDC151 gene. This alteration results from a A to G substitution at nucleotide position 526, causing the arginine (R) at amino acid position 176 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.52

T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.6

D;.

REVEL

Benign

0.18

Sift

Uncertain

0.024

D;.

Sift4G

Uncertain

0.011

D;D

Polyphen

0.19

B;.

Vest4

0.28

MVP

0.77

MPC

0.77

ClinPred

0.058

GERP RS

1.1

Varity_R

0.19

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over