rs762033637

Variant names:

• chr19-11426193-T-C
• rs762033637
• NM_145045.5:c.914A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_145045.5(ODAD3):​c.914A>G​(p.Lys305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.700
• Publications: 2 publications found

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]

ODAD3 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 30

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17688766).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000314 (459/1461440) while in subpopulation NFE AF = 0.00039 (434/1111880). AF 95% confidence interval is 0.00036. There are 0 homozygotes in GnomAdExome4. There are 209 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145045.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD3	NM_145045.5	MANE Select	c.914A>G	p.Lys305Arg	missense	Exon 7 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.752A>G	p.Lys251Arg	missense	Exon 7 of 13	NP_001289382.1
	ODAD3	NM_001302454.2		c.734A>G	p.Lys245Arg	missense	Exon 5 of 11	NP_001289383.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD3	ENST00000356392.9	TSL:1 MANE Select	c.914A>G	p.Lys305Arg	missense	Exon 7 of 13	ENSP00000348757.3
	ODAD3	ENST00000591179.5	TSL:1	c.734A>G	p.Lys245Arg	missense	Exon 5 of 11	ENSP00000466800.1
	ODAD3	ENST00000586836.5	TSL:2	c.341A>G	p.Lys114Arg	missense	Exon 7 of 13	ENSP00000467429.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000141 AC: 35 AN: 248542 AF XY: 0.000119

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1461440 Hom.: 0 Cov.: 33 AF XY: 0.000287 AC XY: 209 AN XY: 727058

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000390 AC: 434 AN: 1111880

Other (OTH) AF: 0.000398 AC: 24 AN: 60364

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74302

African (AFR) AF: 0.000121 AC: 5 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Primary ciliary dyskinesia 30 (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.0090	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.70
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T
Sift4G	Benign	0.52	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.75
MPC		1.2
ClinPred		0.23	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.38
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs762033637; hg19: chr19-11537013; COSMIC: COSV62698344; COSMIC: COSV62698344;