Genetic Variant ODAD3:p.Arg133His (chr19-11430745-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145045.5(ODAD3):c.398G>A(p.Arg133His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,614,008 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. R133C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

ODAD3
NM_145045.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.270

Publications

0 publications found

Variant links:

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 links:

PRKCSH (HGNC:9411): (PRKCSH beta subunit of glucosidase II) This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

PRKCSH Gene-Disease associations (from GenCC):

polycystic liver disease 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, Genomics England PanelApp

PRKCSH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003414899).

BP6

Variant 19-11430745-C-T is Benign according to our data. Variant chr19-11430745-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 544218.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 = 0.0016 (244/152136) while in subpopulation AFR AF = 0.00557 (231/41502). AF 95% confidence interval is 0.00498. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ODAD3	NM_145045.5	MANE Select	c.398G>A	p.Arg133His	missense	Exon 3 of 13	NP_659482.3
ODAD3	NM_001302453.1		c.236G>A	p.Arg79His	missense	Exon 3 of 13	NP_001289382.1
ODAD3	NM_001302454.2		c.366+154G>A		intron	N/A	NP_001289383.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ODAD3	ENST00000356392.9	TSL:1 MANE Select	c.398G>A	p.Arg133His	missense	Exon 3 of 13	ENSP00000348757.3
ODAD3	ENST00000591179.5	TSL:1	c.366+154G>A		intron	N/A	ENSP00000466800.1
ODAD3	ENST00000861507.1		c.398G>A	p.Arg133His	missense	Exon 3 of 12	ENSP00000531566.1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00534

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

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:

0.00

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000473

AC:

118

AN:

249486

AF XY:

0.000355

show subpopulations

Gnomad AFR exome

AF:

0.00626

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00630

AC:

211

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111994

Other (OTH)

AF:

0.000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152136

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00557

AC:

231

AN:

41502

American (AMR)

AF:

0.000722

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000679

Hom.:

Bravo

AF:

0.00179

ESP6500AA

AF:

0.00430

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000512

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 30 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.8

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0039

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.22

M_CAP

Benign

0.018

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.63

PhyloP100

-0.27

PrimateAI

Benign

0.22

PROVEAN

Benign

0.090

REVEL

Benign

0.11

Sift

Benign

0.43

Sift4G

Benign

0.17

Polyphen

0.0070

Vest4

0.17

MVP

0.46

MPC

0.56

ClinPred

0.0039

GERP RS

-1.7

Varity_R

0.023

gMVP

0.050

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over