19-48318481-C-G

Position:

• chr19-48318481-C-G

Variant summary

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

The NM_001364171.2(ODAD1):​c.266G>C​(p.Arg89Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,551,646 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (23 hom.)
• Consequence: ODAD1 NM_001364171.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.277

Genes affected

ODAD1 (HGNC:26560): (outer dynein arm docking complex subunit 1) This gene encodes a coiled-coil domain-containing protein that is a component of the outer dynein arm docking complex in cilia cells. Mutations in this gene may cause primary ciliary dyskinesia 20. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039197803).
• BP6: Variant 19-48318481-C-G is Benign according to our data. Variant chr19-48318481-C-G is described in ClinVar as [Benign]. Clinvar id is 241874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48318481-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00168 (256/152282) while in subpopulation EAS AF= 0.0471 (244/5182). AF 95% confidence interval is 0.0422. There are 6 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD1	NM_001364171.2	c.266G>C	p.Arg89Pro	missense_variant	5/16	ENST00000674294.1
ODAD1	NM_144577.4	c.155G>C	p.Arg52Pro	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD1	ENST00000674294.1	c.266G>C	p.Arg89Pro	missense_variant	5/16		NM_001364171.2	P2

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152164 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0470

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00395 AC: 615 AN: 155732 Hom.: 18 AF XY: 0.00380 AC XY: 314 AN XY: 82612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0532

Gnomad SAS exome AF: 0.000746

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000664

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.000975 AC: 1365 AN: 1399364 Hom.: 23 Cov.: 31 AF XY: 0.000955 AC XY: 659 AN XY: 690192

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0315

Gnomad4 SAS exome AF: 0.000694

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000436

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152282 Hom.: 6 Cov.: 31 AF XY: 0.00189 AC XY: 141 AN XY: 74460

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0471

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.00192

ExAC AF: 0.00203 AC: 52

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 18, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.053	T
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.39
MPC		0.92
ClinPred		0.067	T
GERP RS		2.3
Varity_R		0.32
gMVP		0.77

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: rs58966182; hg19: chr19-48821738;