Genetic Variant RIN1:p.Arg779Gln (chr11-66332292-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_004292.3(RIN1):c.2336G>A(p.Arg779Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RIN1
NM_004292.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.96

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024991184).

BP6

Variant 11-66332292-C-T is Benign according to our data. Variant chr11-66332292-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3433480.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN1	NM_004292.3 link	c.2336G>A	p.Arg779Gln	missense_variant	Exon 10 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.2336G>A	p.Arg779Gln	missense_variant	Exon 10 of 10	1	NM_004292.3	ENSP00000310406.4		Q13671-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251430

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0050

DANN

Benign

0.72

DEOGEN2

Benign

0.069

T;.

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.81

N;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.0060

Sift

Benign

0.82

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.0010

B;B

Vest4

0.043

MutPred

0.19

Gain of relative solvent accessibility (P = 0.0275);.;

MVP

0.088

MPC

0.30

ClinPred

0.024

GERP RS

-8.9

Varity_R

0.010

gMVP

0.032

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