rs762033637

Positions:

chr19-11426193-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_145045.5(ODAD3):c.914A>G(p.Lys305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

ODAD3
NM_145045.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.700

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17688766).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000314 (459/1461440) while in subpopulation NFE AF= 0.00039 (434/1111880). AF 95% confidence interval is 0.00036. There are 0 homozygotes in gnomad4_exome. There are 209 alleles in male gnomad4_exome subpopulation. Median coverage is 33. 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	Protein
ODAD3	NM_145045.5 linkuse as main transcript	c.914A>G	p.Lys305Arg	missense_variant	7/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1 linkuse as main transcript	c.752A>G	p.Lys251Arg	missense_variant	7/13		NP_001289382.1
ODAD3	NM_001302454.2 linkuse as main transcript	c.734A>G	p.Lys245Arg	missense_variant	5/11		NP_001289383.1
ODAD3	XM_017026241.2 linkuse as main transcript	c.904+10A>G		intron_variant			XP_016881730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9 linkuse as main transcript	c.914A>G	p.Lys305Arg	missense_variant	7/13	1	NM_145045.5	ENSP00000348757	P2	A5D8V7-1
ODAD3	ENST00000591179.5 linkuse as main transcript	c.734A>G	p.Lys245Arg	missense_variant	5/11	1		ENSP00000466800	A2
ODAD3	ENST00000586836.5 linkuse as main transcript	c.341A>G	p.Lys114Arg	missense_variant	7/13	2		ENSP00000467429	A2
ODAD3	ENST00000591345.5 linkuse as main transcript	c.*833A>G		3_prime_UTR_variant, NMD_transcript_variant	8/14	5		ENSP00000467313

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000141

AC:

AN:

248542

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134968

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000314

AC:

459

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

209

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000390

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000151

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 30

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 305 of the CCDC151 protein (p.Lys305Arg). This variant is present in population databases (rs762033637, gnomAD 0.02%). 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: 228474). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Revvity Omics, Revvity	Aug 14, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2015

The p.Lys305Arg variant in CCDC151 has not been previously reported in individua ls with primary ciliary dyskinesia, but has been identified in 10/63026 of Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org). Four other species (American alligator, tetradon, stickleback, and f ruitfly) carry an arginine (Arg) at this position, raising the posibility that t his chnage may be tolerated. However, this information is not predictive enough to rule out pathogenicity and additional computational prediction tools do not p rovide strong support for or against an impact to the protein. In summary, the c linical significance of the p.Lys305Arg variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.914A>G (p.K305R) alteration is located in exon 7 (coding exon 7) of the CCDC151 gene. This alteration results from a A to G substitution at nucleotide position 914, causing the lysine (K) at amino acid position 305 to be replaced by an arginine (R). 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

0.085

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T;.

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Uncertain

-0.0090

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.61

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.0

N;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.13

T;.;.

Sift4G

Benign

0.52

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.32

MVP

0.75

MPC

1.2

ClinPred

0.23

GERP RS

3.4

Varity_R

0.17

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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