19-11423933-G-T

Variant names:

• chr19-11423933-G-T
• rs1555721837
• NM_145045.5:c.1060C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145045.5(ODAD3):​c.1060C>A​(p.Gln354Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1060C>A	p.Gln354Lys	missense	Exon 8 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.898C>A	p.Gln300Lys	missense	Exon 8 of 13	NP_001289382.1	A5D8V7-2
	ODAD3	NM_001302454.2		c.880C>A	p.Gln294Lys	missense	Exon 6 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.1060C>A	p.Gln354Lys	missense	Exon 8 of 13	ENSP00000348757.3	A5D8V7-1
	ODAD3	ENST00000591179.5	TSL:1	c.880C>A	p.Gln294Lys	missense	Exon 6 of 11	ENSP00000466800.1	K7EN59
	ODAD3	ENST00000861507.1		c.958C>A	p.Gln320Lys	missense	Exon 7 of 12	ENSP00000531566.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461304 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0050	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Benign	0.19	T
Sift4G	Benign	0.66	T
Polyphen		0.66	P
Vest4		0.54
MutPred		0.60		Gain of ubiquitination at Q354 (P = 0.0162)
MVP		0.73
MPC		0.68
ClinPred		0.67	D
GERP RS		4.2
Varity_R		0.21
gMVP		0.43
Mutation Taster		=86/14	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: rs1555721837; hg19: chr19-11534602;