11-8126740-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001206671.4(RIC3):c.589G>T(p.Val197Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,068 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (12 hom.)
• Consequence: RIC3 NM_001206671.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.75

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009019583).
• BP6: Variant 11-8126740-C-A is Benign according to our data. Variant chr11-8126740-C-A is described in ClinVar as [Benign]. Clinvar id is 788363.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-8126740-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIC3	NM_001206671.4	c.589G>T	p.Val197Phe	missense_variant	5/6	ENST00000309737.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIC3	ENST00000309737.11	c.589G>T	p.Val197Phe	missense_variant	5/6	1	NM_001206671.4	A1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152098 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00301 AC: 758 AN: 251460 Hom.: 3 AF XY: 0.00300 AC XY: 408 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00183 AC: 2676 AN: 1461852 Hom.: 12 Cov.: 31 AF XY: 0.00189 AC XY: 1371 AN XY: 727222

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152216 Hom.: 4 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74432

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00112

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00266 AC: 323

EpiCase AF: 0.00169

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.87
MVP		0.70
MPC		0.39
ClinPred		0.047	T
GERP RS		5.7
Varity_R		0.39
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs139685245; hg19: chr11-8148287;