rs201977207

Variant names:

• chr19-11426909-C-A
• rs201977207
• NM_145045.5:c.576G>T

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.576G>T​(p.Met192Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,609,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0850
• Publications: 1 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=0.03209251).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000124 (181/1457578) while in subpopulation AMR AF = 0.000717 (32/44614). AF 95% confidence interval is 0.000522. There are 0 homozygotes in GnomAdExome4. There are 99 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. 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.576G>T	p.Met192Ile	missense	Exon 4 of 13	NP_659482.3
	ODAD3	NM_001302453.1		c.414G>T	p.Met138Ile	missense	Exon 4 of 13	NP_001289382.1	A5D8V7-2
	ODAD3	NM_001302454.2		c.498G>T	p.Met166Ile	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.576G>T	p.Met192Ile	missense	Exon 4 of 13	ENSP00000348757.3	A5D8V7-1
	ODAD3	ENST00000591179.5	TSL:1	c.498G>T	p.Met166Ile	missense	Exon 3 of 11	ENSP00000466800.1	K7EN59
	ODAD3	ENST00000586836.5	TSL:2	c.3G>T	p.Met1?	start_lost	Exon 4 of 13	ENSP00000467429.1	K7EPK8

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 54 AN: 246490 AF XY: 0.000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000640

Gnomad ASJ exome AF: 0.000602

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1457578 Hom.: 0 Cov.: 33 AF XY: 0.000137 AC XY: 99 AN XY: 724718

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.000717 AC: 32 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.000614 AC: 16 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51684

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.0000982 AC: 109 AN: 1110068

Other (OTH) AF: 0.000299 AC: 18 AN: 60228

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Primary ciliary dyskinesia 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.2
DANN	Benign	0.60
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.79	N
PhyloP100		-0.085
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.16
Sift	Benign	0.43	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.28		Loss of MoRF binding (P = 0.0865)
MVP		0.60
MPC		0.49
ClinPred		0.021	T
GERP RS		-2.0
Varity_R		0.042
gMVP		0.13
Mutation Taster		=112/88	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: rs201977207; hg19: chr19-11537729;