Variant 11-8140017-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_001206671.4(RIC3):c.301C>T(p.Pro101Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,614,006 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0029 ( 10 hom. )

Consequence

RIC3
NM_001206671.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.53

Variant links:

Genes affected

RIC3 (HGNC:30338): (RIC3 acetylcholine receptor chaperone) This gene encodes a member of the resistance to inhibitors of cholinesterase 3-like family which functions as a chaperone of specific 5-hydroxytryptamine type 3 receptor and nicotinic acetylcholine receptor subtypes. The encoded protein influences the folding and assembly of these receptor subunits in the endoplasmic reticulum and expression on the cell surface. This protein contains an N-terminal transmembrane domain, a proline-rich spacer, and a cytosolic C-terminal coiled-coil domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

RIC3 links:

RIC3 (HGNC:):

RIC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.027805716).

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIC3	NM_001206671.4 linkuse as main transcript	c.301C>T	p.Pro101Ser	missense_variant	2/6	ENST00000309737.11	NP_001193600.1	Q7Z5B4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIC3	ENST00000309737.11 linkuse as main transcript	c.301C>T	p.Pro101Ser	missense_variant	2/6	1	NM_001206671.4	ENSP00000308820.6		Q7Z5B4-1

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000918

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00257

AC:

647

AN:

251388

Hom.:

AF XY:

0.00253

AC XY:

344

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00322

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00286

AC:

4186

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

2047

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00165

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.00304

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152154

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00297

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.00205

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00396

AC:

ExAC

AF:

0.00273

AC:

332

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00327

EpiControl

AF:

0.00338

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 05, 2024

PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

.;T;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.028

T;T;T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.6

M;M;M;.;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.2

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.92

MVP

0.88

MPC

0.35

ClinPred

0.045

GERP RS

5.6

Varity_R

0.85

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over