rs114111020

chr19-48297464-C-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.1636G>A(p.Ala546Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,600,422 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A546A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: ODAD1 NM_001364171.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.04

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=0.002634257).
• BP6: Variant 19-48297464-C-T is Benign according to our data. Variant chr19-48297464-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00895 (1363/152214) while in subpopulation AFR AF= 0.0312 (1295/41522). AF 95% confidence interval is 0.0298. There are 17 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD1	NM_001364171.2	c.1636G>A	p.Ala546Thr	missense_variant	16/16	ENST00000674294.1
ODAD1	NM_144577.4	c.1525G>A	p.Ala509Thr	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD1	ENST00000674294.1	c.1636G>A	p.Ala546Thr	missense_variant	16/16		NM_001364171.2	P2

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1360 AN: 152096 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00237 AC: 546 AN: 230062 Hom.: 7 AF XY: 0.00172 AC XY: 217 AN XY: 126462

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000805

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000894

GnomAD4 exome AF: 0.00102 AC: 1476 AN: 1448208 Hom.: 27 Cov.: 62 AF XY: 0.000933 AC XY: 672 AN XY: 720558

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000782

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000451

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00895 AC: 1363 AN: 152214 Hom.: 17 Cov.: 33 AF XY: 0.00869 AC XY: 647 AN XY: 74424

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00323 Hom.: 1

Bravo AF: 0.0101

ESP6500AA AF: 0.0323 AC: 142

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00277 AC: 332

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2016	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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 16, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.0060
Dann	Benign	0.45
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.017
Sift	Benign	0.64	T
Sift4G	Benign	0.21	T
Polyphen		0.41	B
Vest4		0.10
MVP		0.16
MPC		0.19
ClinPred		0.0018	T
GERP RS		-4.3
Varity_R		0.025
gMVP		0.075

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: rs114111020; hg19: chr19-48800721; COSMIC: COSV59558321;