rs148823991

chr19-48298021-G-Achr19-48298021-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001364171.2(ODAD1):c.1481C>T(p.Pro494Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,116 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P494S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: ODAD1 NM_001364171.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.193

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008339912).
• BP6: Variant 19-48298021-G-A is Benign according to our data. Variant chr19-48298021-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (301/152218) while in subpopulation NFE AF= 0.00368 (250/68008). AF 95% confidence interval is 0.0033. There are 0 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD1	NM_001364171.2	c.1481C>T	p.Pro494Leu	missense_variant	14/16	ENST00000674294.1
ODAD1	NM_144577.4	c.1370C>T	p.Pro457Leu	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD1	ENST00000674294.1	c.1481C>T	p.Pro494Leu	missense_variant	14/16		NM_001364171.2	P2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00171 AC: 428 AN: 250134 Hom.: 1 AF XY: 0.00181 AC XY: 245 AN XY: 135318

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00320 AC: 4673 AN: 1460898 Hom.: 11 Cov.: 33 AF XY: 0.00305 AC XY: 2219 AN XY: 726800

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000742

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.000489

Gnomad4 NFE exome AF: 0.00389

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.00185 AC XY: 138 AN XY: 74400

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00266 Hom.: 0

Bravo AF: 0.00193

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00171 AC: 208

EpiCase AF: 0.00322

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ODAD1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.56
Dann	Benign	0.27
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.041
Sift	Benign	0.30	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.094
MVP		0.21
MPC		0.21
ClinPred		0.0069	T
GERP RS		0.086
Varity_R		0.048
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148823991; hg19: chr19-48801278;