Genetic Variant RIN1:p.Val546Ile (chr11-66333614-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004292.3(RIN1):c.1636G>A(p.Val546Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,512 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0062 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 14 hom. )

Consequence

RIN1
NM_004292.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

RIN1 (HGNC:18749): (Ras and Rab interactor 1) Predicted to enable small GTPase binding activity. Predicted to be involved in endocytosis; regulation of catalytic activity; and signal transduction. Predicted to act upstream of or within associative learning; memory; and negative regulation of synaptic plasticity. Located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RIN1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008645862).

BP6

Variant 11-66333614-C-T is Benign according to our data. Variant chr11-66333614-C-T is described in ClinVar as [Benign]. Clinvar id is 720437.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00622 (948/152328) while in subpopulation AFR AF= 0.0197 (821/41574). AF 95% confidence interval is 0.0186. There are 11 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN1	NM_004292.3 link	c.1636G>A	p.Val546Ile	missense_variant	Exon 8 of 10	ENST00000311320.9	NP_004283.2	Q13671-1A0A0S2Z4U0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN1	ENST00000311320.9 link	c.1636G>A	p.Val546Ile	missense_variant	Exon 8 of 10	1	NM_004292.3	ENSP00000310406.4		Q13671-1

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

948

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00210

AC:

527

AN:

250704

Hom.:

AF XY:

0.00172

AC XY:

234

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00329

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000865

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00119

AC:

1743

AN:

1461184

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

835

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.0198

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.0000568

Gnomad4 NFE exome

AF:

0.000701

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.00622

AC:

948

AN:

152328

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0197

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00172

Hom.:

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.064

T;D

Polyphen

0.99

D;D

Vest4

0.49

MVP

0.48

MPC

0.63

ClinPred

0.027

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.34

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

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