rs762033637

chr19-11426193-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.700

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]

ACMG classification

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	UniProt
ODAD3	NM_145045.5	c.914A>G	p.Lys305Arg	missense_variant	7/13	ENST00000356392.9
ODAD3	NM_001302453.1	c.752A>G	p.Lys251Arg	missense_variant	7/13
ODAD3	NM_001302454.2	c.734A>G	p.Lys245Arg	missense_variant	5/11
ODAD3	XM_017026241.2	c.904+10A>G		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152118 Hom.: 0 Cov.: 31

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: 35 AN: 248542 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134968

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.: 0 Cov.: 33 AF XY: 0.000287 AC XY: 209 AN XY: 727058

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: 23 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74302

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.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 30 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -

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	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;.
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	-0.0090	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.61	D;D;D;D
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs762033637; hg19: chr19-11537013; COSMIC: COSV62698344; COSMIC: COSV62698344;