19-11427004-C-T

Position:

• chr19-11427004-C-T

Variant summary

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

The NM_145045.5(ODAD3):​c.481G>A​(p.Val161Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.186

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=0.079865545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD3	NM_145045.5	c.481G>A	p.Val161Met	missense_variant	4/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1	c.319G>A	p.Val107Met	missense_variant	4/13		NP_001289382.1
ODAD3	NM_001302454.2	c.403G>A	p.Val135Met	missense_variant	3/11		NP_001289383.1
ODAD3	XM_017026241.2	c.481G>A	p.Val161Met	missense_variant	4/9		XP_016881730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9	c.481G>A	p.Val161Met	missense_variant	4/13	1	NM_145045.5	ENSP00000348757	P2
ODAD3	ENST00000591179.5	c.403G>A	p.Val135Met	missense_variant	3/11	1		ENSP00000466800	A2
ODAD3	ENST00000586836.5	c.-93G>A		5_prime_UTR_variant	4/13	2		ENSP00000467429	A2
ODAD3	ENST00000591345.5	c.*400G>A		3_prime_UTR_variant, NMD_transcript_variant	5/14	5		ENSP00000467313

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449666 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721342

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

May 26, 2017

In summary, this variant has uncertain impact on CCDC151 function. The available evidence is currently insufficient to determine its role 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a CCDC151-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 161 of the CCDC151 protein (p.Val161Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.0023	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.38	N;.
REVEL	Benign	0.20
Sift	Benign	0.29	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.77	P;.
Vest4		0.16
MutPred		0.21		Loss of methylation at K162 (P = 0.032);.;
MVP		0.77
MPC		0.53
ClinPred		0.19	T
GERP RS		1.7
Varity_R		0.038
gMVP		0.095

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: rs1555723194; hg19: chr19-11537824;