rs143192349

chr19-11431011-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_145045.5(ODAD3):c.254G>A(p.Arg85Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,614,066 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (34 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.24

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014934778).
• BP6: Variant 19-11431011-C-T is Benign according to our data. Variant chr19-11431011-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414142.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=1}. Variant chr19-11431011-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00344 (523/152196) while in subpopulation SAS AF= 0.0079 (38/4812). AF 95% confidence interval is 0.00591. There are 1 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD3	NM_145045.5	c.254G>A	p.Arg85Gln	missense_variant	2/13	ENST00000356392.9
ODAD3	NM_001302453.1	c.92G>A	p.Arg31Gln	missense_variant	2/13
ODAD3	NM_001302454.2	c.254G>A	p.Arg85Gln	missense_variant	2/11
ODAD3	XM_017026241.2	c.254G>A	p.Arg85Gln	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD3	ENST00000356392.9	c.254G>A	p.Arg85Gln	missense_variant	2/13	1	NM_145045.5	P2

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152080 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00789

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00369 AC: 920 AN: 249482 Hom.: 6 AF XY: 0.00396 AC XY: 536 AN XY: 135364

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00647

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00556 AC: 8133 AN: 1461870 Hom.: 34 Cov.: 35 AF XY: 0.00568 AC XY: 4134 AN XY: 727242

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00773

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00633

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152196 Hom.: 1 Cov.: 30 AF XY: 0.00323 AC XY: 240 AN XY: 74406

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00790

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00584

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00448 Hom.: 3

Bravo AF: 0.00324

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000524 AC: 2

ESP6500EA AF: 0.00497 AC: 41

ExAC AF: 0.00413 AC: 499

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 30 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.254G>A (p.R85Q) alteration is located in exon 2 (coding exon 2) of the CCDC151 gene. This alteration results from a G to A substitution at nucleotide position 254, causing the arginine (R) at amino acid position 85 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.22	T;T
Polyphen		0.99	D;.
Vest4		0.71
MVP		0.84
MPC		1.4
ClinPred		0.036	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143192349; hg19: chr19-11541831; COSMIC: COSV52952746; COSMIC: COSV52952746;