chr19-11421777-G-C

Position:

• chr19-11421777-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000356392.9(ODAD3):​c.1490C>G​(p.Pro497Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ODAD3 ENST00000356392.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.563

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17839429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD3	NM_145045.5	c.1490C>G	p.Pro497Arg	missense_variant	11/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1	c.1328C>G	p.Pro443Arg	missense_variant	11/13		NP_001289382.1
ODAD3	NM_001302454.2	c.1310C>G	p.Pro437Arg	missense_variant	9/11		NP_001289383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9	c.1490C>G	p.Pro497Arg	missense_variant	11/13	1	NM_145045.5	ENSP00000348757	P2
ODAD3	ENST00000591179.5	c.1310C>G	p.Pro437Arg	missense_variant	9/11	1		ENSP00000466800	A2
ODAD3	ENST00000586836.5	c.917C>G	p.Pro306Arg	missense_variant	11/13	2		ENSP00000467429	A2
ODAD3	ENST00000591345.5	c.*1409C>G		3_prime_UTR_variant, NMD_transcript_variant	12/14	5		ENSP00000467313

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2017

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 missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CCDC151-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 497 of the CCDC151 protein (p.Pro497Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0070	T;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.85	N;.;.
REVEL	Benign	0.10
Sift	Benign	0.12	T;.;.
Sift4G	Benign	0.81	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.43
MutPred		0.38		Loss of catalytic residue at D493 (P = 0.0464);.;.;
MVP		0.42
MPC		1.2
ClinPred		0.42	T
GERP RS		-6.2
Varity_R		0.037
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1340885760; hg19: chr19-11532445;