rs143287033

Variant names:

• chr19-11426959-T-C
• rs143287033
• NM_145045.5:c.526A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11426959-T-C
• chr19-11426959-T-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_145045.5(ODAD3):​c.526A>G​(p.Arg176Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,608,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0800
• 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]

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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03640431).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000328 (50/152310) while in subpopulation AMR AF = 0.00072 (11/15286). AF 95% confidence interval is 0.000403. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODAD3	NM_145045.5	MANE Select	c.526A>G	p.Arg176Gly	missense	Exon 4 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.364A>G	p.Arg122Gly	missense	Exon 4 of 13	NP_001289382.1	A5D8V7-2
	ODAD3	NM_001302454.2		c.448A>G	p.Arg150Gly	missense	Exon 3 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.526A>G	p.Arg176Gly	missense	Exon 4 of 13	ENSP00000348757.3	A5D8V7-1
	ODAD3	ENST00000591179.5	TSL:1	c.448A>G	p.Arg150Gly	missense	Exon 3 of 11	ENSP00000466800.1	K7EN59
	ODAD3	ENST00000861507.1		c.526A>G	p.Arg176Gly	missense	Exon 4 of 12	ENSP00000531566.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000334 AC: 81 AN: 242558 AF XY: 0.000287

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.000640

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000350 AC: 510 AN: 1456568 Hom.: 1 Cov.: 33 AF XY: 0.000350 AC XY: 254 AN XY: 724880

African (AFR) AF: 0.000209 AC: 7 AN: 33470

American (AMR) AF: 0.000716 AC: 32 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48730

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5746

European-Non Finnish (NFE) AF: 0.000356 AC: 396 AN: 1111614

Other (OTH) AF: 0.000464 AC: 28 AN: 60318

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152310 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68024

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

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000382

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia 30 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.080
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.011	D
Polyphen		0.19	B
Vest4		0.28
MVP		0.77
MPC		0.77
ClinPred		0.058	T
GERP RS		1.1
Varity_R		0.19
gMVP		0.18
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs143287033; hg19: chr19-11537779;