rs143192349

Variant names:

• chr19-11431011-C-T
• rs143192349
• NM_145045.5:c.254G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_145045.5(ODAD3):​c.254G>A​(p.Arg85Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,614,066 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (34 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.24
• Publications: 9 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]

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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014934778).
• BP6: Variant 19-11431011-C-T is Benign according to our data. Variant chr19-11431011-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414142.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00344 (523/152196) while in subpopulation SAS AF = 0.0079 (38/4812). AF 95% confidence interval is 0.00591. There are 1 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD3	NM_145045.5	MANE Select	c.254G>A	p.Arg85Gln	missense	Exon 2 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.92G>A	p.Arg31Gln	missense	Exon 2 of 13	NP_001289382.1	A5D8V7-2
	ODAD3	NM_001302454.2		c.254G>A	p.Arg85Gln	missense	Exon 2 of 11	NP_001289383.1	K7EN59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD3	ENST00000356392.9	TSL:1 MANE Select	c.254G>A	p.Arg85Gln	missense	Exon 2 of 13	ENSP00000348757.3	A5D8V7-1
	ODAD3	ENST00000591179.5	TSL:1	c.254G>A	p.Arg85Gln	missense	Exon 2 of 11	ENSP00000466800.1	K7EN59
	PRKCSH	ENST00000916401.1		c.-164C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 22	ENSP00000586460.1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152080 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00789

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00369 AC: 920 AN: 249482 AF XY: 0.00396

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00556 AC: 8133 AN: 1461870 Hom.: 34 Cov.: 35 AF XY: 0.00568 AC XY: 4134 AN XY: 727242

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00773 AC: 667 AN: 86258

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53400

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00633 AC: 7039 AN: 1112010

Other (OTH) AF: 0.00434 AC: 262 AN: 60394

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152196 Hom.: 1 Cov.: 30 AF XY: 0.00323 AC XY: 240 AN XY: 74406

African (AFR) AF: 0.000915 AC: 38 AN: 41540

American (AMR) AF: 0.00124 AC: 19 AN: 15270

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00790 AC: 38 AN: 4812

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 68004

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00459 Hom.: 7

Bravo AF: 0.00324

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000524 AC: 2

ESP6500EA AF: 0.00497 AC: 41

ExAC AF: 0.00413 AC: 499

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Primary ciliary dyskinesia 30 (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.2
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.71
MVP		0.84
MPC		1.4
ClinPred		0.036	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.49
Mutation Taster		=299/1	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: rs143192349; hg19: chr19-11541831; COSMIC: COSV52952746; COSMIC: COSV52952746;