Genetic Variant RIN3:p.Pro477Ser (chr14-92652478-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024832.5(RIN3):c.1429C>T(p.Pro477Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,614,078 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.040 ( 412 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 395 hom. )

Consequence

RIN3
NM_024832.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

6 publications found

Variant links:

Genes affected

RIN3 (HGNC:18751): (Ras and Rab interactor 3) Summary: This protein encoded by this gene is a member of the RIN family of Ras interaction-interference proteins, which are binding partners to the RAB5 small GTPases. The protein functions as a guanine nucleotide exchange for RAB5B and RAB31. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

RIN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0015961528).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5 link	c.1429C>T	p.Pro477Ser	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3	Q8TB24-1Q6NSK7Q86U22
RIN3	NM_001319987.2 link	c.1204C>T	p.Pro402Ser	missense_variant	Exon 5 of 9		NP_001306916.1	Q8TB24Q6ZRC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN3	ENST00000216487.12 link	c.1429C>T	p.Pro477Ser	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7		Q8TB24-1

Frequencies

GnomAD3 genomes

AF:

0.0400

AC:

6090

AN:

152112

Hom.:

412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0102

AC:

2555

AN:

251272

AF XY:

0.00743

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00399

AC:

5830

AN:

1461848

Hom.:

395

Cov.:

AF XY:

0.00341

AC XY:

2481

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.143

AC:

4799

AN:

33478

American (AMR)

AF:

0.00680

AC:

304

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000160

AC:

178

AN:

1112008

Other (OTH)

AF:

0.00810

AC:

489

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

330

659

989

1318

1648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0401

AC:

6102

AN:

152230

Hom.:

412

Cov.:

AF XY:

0.0381

AC XY:

2839

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.139

AC:

5786

AN:

41504

American (AMR)

AF:

0.0142

AC:

217

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68018

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

268

537

805

1074

1342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0137

Hom.:

253

Bravo

AF:

0.0454

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.133

AC:

585

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0131

AC:

1588

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0076

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

1.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.058

Sift

Benign

0.19

T;.

Sift4G

Uncertain

0.037

D;D

Polyphen

0.47

P;.

Vest4

0.33

MPC

0.37

ClinPred

0.0041

GERP RS

3.6

PromoterAI

0.072

Neutral

(source)

Varity_R

0.031

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over