rs538588580

Positions:

• chr19-48311585-G-A
• chr19-48311585-G-T

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.565C>T​(p.Arg189Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,550,828 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: ODAD1 NM_001364171.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.17

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=0.015157074).
• BP6: Variant 19-48311585-G-A is Benign according to our data. Variant chr19-48311585-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 413799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48311585-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000269 (41/152158) while in subpopulation SAS AF= 0.00808 (39/4824). AF 95% confidence interval is 0.00608. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD1	NM_001364171.2	c.565C>T	p.Arg189Cys	missense_variant	7/16	ENST00000674294.1	NP_001351100.1
ODAD1	NM_144577.4	c.454C>T	p.Arg152Cys	missense_variant	5/14		NP_653178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD1	ENST00000674294.1	c.565C>T	p.Arg189Cys	missense_variant	7/16		NM_001364171.2	ENSP00000501363	P2

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000927 AC: 145 AN: 156446 Hom.: 0 AF XY: 0.00124 AC XY: 103 AN XY: 82932

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00619

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000411 AC: 575 AN: 1398670 Hom.: 4 Cov.: 30 AF XY: 0.000604 AC XY: 417 AN XY: 689882

Gnomad4 AFR exome AF: 0.0000950

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00663

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.000500

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000673 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.00203 AC: 56

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.53		Loss of MoRF binding (P = 0.0283);
MVP		0.97
MPC		0.91
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.096
gMVP		0.34

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: rs538588580; hg19: chr19-48814842;