rs61741137

chr19-11434844-A-G

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.173T>C(p.Phe58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,158 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (5 hom., cov: 33)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.509

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=0.0034710765).
• BP6: Variant 19-11434844-A-G is Benign according to our data. Variant chr19-11434844-A-G is described in ClinVar as [Benign]. Clinvar id is 221005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11434844-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00737 (1122/152286) while in subpopulation NFE AF= 0.0125 (848/68012). AF 95% confidence interval is 0.0118. There are 5 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD3	NM_145045.5	c.173T>C	p.Phe58Ser	missense_variant	1/13	ENST00000356392.9
ODAD3	NM_001302454.2	c.173T>C	p.Phe58Ser	missense_variant	1/11
ODAD3	XM_017026241.2	c.173T>C	p.Phe58Ser	missense_variant	1/9
ODAD3	NM_001302453.1	c.82+846T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD3	ENST00000356392.9	c.173T>C	p.Phe58Ser	missense_variant	1/13	1	NM_145045.5	P2

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152168 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00855 AC: 2133 AN: 249532 Hom.: 17 AF XY: 0.00892 AC XY: 1208 AN XY: 135384

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00755

Gnomad FIN exome AF: 0.00422

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00908

GnomAD4 exome AF: 0.0127 AC: 18553 AN: 1461872 Hom.: 157 Cov.: 31 AF XY: 0.0126 AC XY: 9151 AN XY: 727234

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00788

Gnomad4 FIN exome AF: 0.00536

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00737 AC: 1122 AN: 152286 Hom.: 5 Cov.: 33 AF XY: 0.00658 AC XY: 490 AN XY: 74470

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0115 Hom.: 8

Bravo AF: 0.00776

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00204 AC: 8

ESP6500EA AF: 0.0122 AC: 101

ExAC AF: 0.00902 AC: 1090

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 30 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ODAD3: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.1
Dann	Benign	0.51
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.0020
Sift	Benign	0.10	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;.
Vest4		0.097
MVP		0.12
MPC		0.89
ClinPred		0.00039	T
GERP RS		-1.6
Varity_R		0.043
gMVP		0.15

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: rs61741137; hg19: chr19-11545665; COSMIC: COSV99372086; COSMIC: COSV99372086;