Genetic Variant RIN1:p.Arg779Leu (chr11-66332292-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004292.3(RIN1):c.2336G>T(p.Arg779Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R779W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RIN1
NM_004292.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.96

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

familial nonmedullary thyroid carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RIN1 links:

ENSG00000254756 (HGNC:):

ENSG00000254756 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03382352).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004292.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIN1	NM_004292.3	MANE Select	c.2336G>T	p.Arg779Leu	missense	Exon 10 of 10	NP_004283.2	A0A0S2Z4U0
RIN1	NM_001363559.2		c.2252G>T	p.Arg751Leu	missense	Exon 10 of 10	NP_001350488.1
RIN1	NM_001363560.2		c.2150G>T	p.Arg717Leu	missense	Exon 10 of 10	NP_001350489.1	Q13671-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIN1	ENST00000311320.9	TSL:1 MANE Select	c.2336G>T	p.Arg779Leu	missense	Exon 10 of 10	ENSP00000310406.4	Q13671-1
RIN1	ENST00000970357.1		c.2183G>T	p.Arg728Leu	missense	Exon 10 of 10	ENSP00000640416.1
RIN1	ENST00000869551.1		c.2150G>T	p.Arg717Leu	missense	Exon 10 of 10	ENSP00000539610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.011

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.11

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.62

M_CAP

Benign

0.0058

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.55

PhyloP100

-3.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.71

REVEL

Benign

0.0060

Sift

Benign

0.27

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.080

MutPred

0.23

Loss of solvent accessibility (P = 0.0606)

MVP

0.040

MPC

0.32

ClinPred

0.049

GERP RS

-8.9

Varity_R

0.028

gMVP

0.082

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over