Variant 11-8137471-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001206671.4(RIC3):c.428C>A(p.Thr143Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000298 in 1,613,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

RIC3
NM_001206671.4 missense, splice_region

Scores

Splicing: ADA: 0.9291

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.33

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10874686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIC3	NM_001206671.4 link	c.428C>A	p.Thr143Asn	missense_variant, splice_region_variant	4/6	ENST00000309737.11	NP_001193600.1	Q7Z5B4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIC3	ENST00000309737.11 link	c.428C>A	p.Thr143Asn	missense_variant, splice_region_variant	4/6	1	NM_001206671.4	ENSP00000308820.6		Q7Z5B4-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

250702

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000940

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.428C>A (p.T143N) alteration is located in exon 4 (coding exon 4) of the RIC3 gene. This alteration results from a C to A substitution at nucleotide position 428, causing the threonine (T) at amino acid position 143 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

.;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.084

T;T;.

Polyphen

0.86

P;P;.

Vest4

0.84

MutPred

0.49

Loss of phosphorylation at T143 (P = 0.0649);Loss of phosphorylation at T143 (P = 0.0649);Loss of phosphorylation at T143 (P = 0.0649);

MVP

0.67

MPC

0.083

ClinPred

0.16

GERP RS

5.1

Varity_R

0.43

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.93

dbscSNV1_RF

Benign

0.67

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

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