chr19-11430719-G-C

Position:

• chr19-11430719-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145045.5(ODAD3):​c.424C>G​(p.Leu142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 1,614,046 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (64 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.07

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010106593).
• BP6: Variant 19-11430719-G-C is Benign according to our data. Variant chr19-11430719-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 414138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11430719-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1816/152174) while in subpopulation AFR AF= 0.0233 (966/41522). AF 95% confidence interval is 0.022. There are 26 homozygotes in gnomad4. There are 921 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD3	NM_145045.5	c.424C>G	p.Leu142Val	missense_variant	3/13	ENST00000356392.9	NP_659482.3
ODAD3	NM_001302453.1	c.262C>G	p.Leu88Val	missense_variant	3/13		NP_001289382.1
ODAD3	XM_017026241.2	c.424C>G	p.Leu142Val	missense_variant	3/9		XP_016881730.1
ODAD3	NM_001302454.2	c.366+180C>G		intron_variant			NP_001289383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD3	ENST00000356392.9	c.424C>G	p.Leu142Val	missense_variant	3/13	1	NM_145045.5	ENSP00000348757	P2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1787 AN: 152056 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00792

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00794 AC: 1981 AN: 249508 Hom.: 14 AF XY: 0.00825 AC XY: 1116 AN XY: 135354

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00795

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00672

Gnomad NFE exome AF: 0.00719

Gnomad OTH exome AF: 0.00727

GnomAD4 exome AF: 0.00814 AC: 11900 AN: 1461872 Hom.: 64 Cov.: 31 AF XY: 0.00830 AC XY: 6038 AN XY: 727234

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00411

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.00545

Gnomad4 NFE exome AF: 0.00795

Gnomad4 OTH exome AF: 0.00778

GnomAD4 genome AF: 0.0119 AC: 1816 AN: 152174 Hom.: 26 Cov.: 32 AF XY: 0.0124 AC XY: 921 AN XY: 74386

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00794

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00772

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00812 Hom.: 1

Bravo AF: 0.0124

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0219 AC: 91

ESP6500EA AF: 0.00704 AC: 59

ExAC AF: 0.00839 AC: 1015

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 30 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0096	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.95	P
Vest4		0.49
MVP		0.81
MPC		1.2
ClinPred		0.013	T
GERP RS		0.47
Varity_R		0.069
gMVP		0.18

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: rs61739927; hg19: chr19-11541539; COSMIC: COSV52953573; COSMIC: COSV52953573;