19-11421158-G-T

Position:

• chr19-11421158-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145045.5(ODAD3):​c.1645C>A​(p.Pro549Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.891

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD3	NM_145045.5	c.1645C>A	p.Pro549Thr	missense_variant	12/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1	c.1483C>A	p.Pro495Thr	missense_variant	12/13		NP_001289382.1
ODAD3	NM_001302454.2	c.1465C>A	p.Pro489Thr	missense_variant	10/11		NP_001289383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9	c.1645C>A	p.Pro549Thr	missense_variant	12/13	1	NM_145045.5	ENSP00000348757.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Nov 06, 2018

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 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"). 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 threonine at codon 549 of the CCDC151 protein (p.Pro549Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.0	D;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.013	D;D;T
Polyphen		1.0	D;.;.
Vest4		0.47
MutPred		0.77		Loss of loop (P = 0.1242);.;.;
MVP		0.58
MPC		1.4
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.41
gMVP		0.25

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

Other links and lift over

dbSNP: rs1599451068; hg19: chr19-11531826;