11-8128206-T-G

Variant names:

• chr11-8128206-T-G
• rs1528133
• NM_001206671.4:c.522-1399A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206671.4(RIC3):​c.522-1399A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 457,318 control chromosomes in the GnomAD database, including 1,891 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.089 (719 hom., cov: 32)
  • Exomes 𝑓: 0.080 (1172 hom.)
• Consequence: RIC3 NM_001206671.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.270
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• movement disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIC3	NM_001206671.4	c.522-1399A>C		intron_variant	Intron 4 of 5	ENST00000309737.11	NP_001193600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIC3	ENST00000309737.11	c.522-1399A>C		intron_variant	Intron 4 of 5	1	NM_001206671.4	ENSP00000308820.6

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13495 AN: 152146 Hom.: 717 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0814

GnomAD2 exomes AF: 0.0857 AC: 11948 AN: 139350 AF XY: 0.0851

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0975

Gnomad EAS exome AF: 0.0501

Gnomad FIN exome AF: 0.0605

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0803 AC: 24492 AN: 305054 Hom.: 1172 Cov.: 0 AF XY: 0.0813 AC XY: 14122 AN XY: 173636

African (AFR) AF: 0.136 AC: 1177 AN: 8630

American (AMR) AF: 0.120 AC: 3266 AN: 27286

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 1058 AN: 10790

East Asian (EAS) AF: 0.0500 AC: 461 AN: 9212

South Asian (SAS) AF: 0.105 AC: 6285 AN: 59744

European-Finnish (FIN) AF: 0.0587 AC: 769 AN: 13094

Middle Eastern (MID) AF: 0.0409 AC: 114 AN: 2788

European-Non Finnish (NFE) AF: 0.0652 AC: 10370 AN: 159082

Other (OTH) AF: 0.0688 AC: 992 AN: 14428

GnomAD4 genome AF: 0.0887 AC: 13505 AN: 152264 Hom.: 719 Cov.: 32 AF XY: 0.0892 AC XY: 6642 AN XY: 74448

African (AFR) AF: 0.132 AC: 5484 AN: 41546

American (AMR) AF: 0.0888 AC: 1359 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.0542 AC: 281 AN: 5184

South Asian (SAS) AF: 0.117 AC: 564 AN: 4818

European-Finnish (FIN) AF: 0.0664 AC: 705 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4492 AN: 68014

Other (OTH) AF: 0.0801 AC: 169 AN: 2110

Alfa AF: 0.0697 Hom.: 702

Bravo AF: 0.0926

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1528133; hg19: chr11-8149753; COSMIC: COSV58302424;