NM_145045.5:c.614C>T

Variant names:

• chr19-11426783-G-A
• rs35061520
• NM_145045.5:c.614C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145045.5(ODAD3):​c.614C>T​(p.Thr205Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,613,892 control chromosomes in the GnomAD database, including 686 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 31)
  • Exomes 𝑓: 0.027 (647 hom.)
• Consequence: ODAD3 NM_145045.5 missense, splice_region
• Scores: Splicing: ADA: 0.0006029
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.533
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039109588).
• BP6: Variant 19-11426783-G-A is Benign according to our data. Variant chr19-11426783-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2972/152238) while in subpopulation NFE AF = 0.0318 (2166/68012). AF 95% confidence interval is 0.0307. There are 39 homozygotes in GnomAd4. There are 1378 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.614C>T	p.Thr205Ile	missense splice_region	Exon 5 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.452C>T	p.Thr151Ile	missense splice_region	Exon 5 of 13	NP_001289382.1	A5D8V7-2
	ODAD3	NM_001302454.2		c.534+90C>T		intron	N/A	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.614C>T	p.Thr205Ile	missense splice_region	Exon 5 of 13	ENSP00000348757.3	A5D8V7-1
	ODAD3	ENST00000591179.5	TSL:1	c.534+90C>T		intron	N/A	ENSP00000466800.1	K7EN59
	ODAD3	ENST00000586836.5	TSL:2	c.41C>T	p.Thr14Ile	missense splice_region	Exon 5 of 13	ENSP00000467429.1	K7EPK8

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2971 AN: 152120 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0209 AC: 5192 AN: 248750 AF XY: 0.0204

Gnomad AFR exome AF: 0.00453

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0273 AC: 39879 AN: 1461654 Hom.: 647 Cov.: 33 AF XY: 0.0266 AC XY: 19334 AN XY: 727118

African (AFR) AF: 0.00460 AC: 154 AN: 33480

American (AMR) AF: 0.0125 AC: 559 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 336 AN: 26128

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

South Asian (SAS) AF: 0.000997 AC: 86 AN: 86258

European-Finnish (FIN) AF: 0.0229 AC: 1219 AN: 53346

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5766

European-Non Finnish (NFE) AF: 0.0325 AC: 36126 AN: 1111880

Other (OTH) AF: 0.0217 AC: 1313 AN: 60376

GnomAD4 genome AF: 0.0195 AC: 2972 AN: 152238 Hom.: 39 Cov.: 31 AF XY: 0.0185 AC XY: 1378 AN XY: 74426

African (AFR) AF: 0.00551 AC: 229 AN: 41540

American (AMR) AF: 0.0154 AC: 236 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.0218 AC: 231 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0318 AC: 2166 AN: 68012

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.0292 Hom.: 112

Bravo AF: 0.0185

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00542 AC: 22

ESP6500EA AF: 0.0301 AC: 252

ExAC AF: 0.0223 AC: 2699

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0300

EpiControl AF: 0.0329

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 30 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.53
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.28
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.093	B
Vest4		0.24
MPC		0.60
ClinPred		0.0051	T
GERP RS		2.5
Varity_R		0.083
gMVP		0.23
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00060
dbscSNV1_RF	Benign	0.0060
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: rs35061520; hg19: chr19-11537603;