Genetic Variant RIN3:p.Thr425Met (chr14-92652323-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.1274C>T(p.Thr425Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,603,976 control chromosomes in the GnomAD database, including 36,207 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.20 ( 3373 hom., cov: 30)

Exomes 𝑓: 0.20 ( 32834 hom. )

Consequence

RIN3
NM_024832.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.211

Publications

31 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.4650822E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5 link	c.1274C>T	p.Thr425Met	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3
RIN3	NM_001319987.2 link	c.1049C>T	p.Thr350Met	missense_variant	Exon 5 of 9		NP_001306916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN3	ENST00000216487.12 link	c.1274C>T	p.Thr425Met	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29882

AN:

151926

Hom.:

3365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.457

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.210

GnomAD2 exomes

AF:

0.241

AC:

58879

AN:

244098

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.171

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.466

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.200

AC:

289887

AN:

1451932

Hom.:

32834

Cov.:

AF XY:

0.205

AC XY:

147516

AN XY:

721118

show subpopulations

African (AFR)

AF:

0.172

AC:

5735

AN:

33274

American (AMR)

AF:

0.272

AC:

11942

AN:

43912

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

4647

AN:

25428

East Asian (EAS)

AF:

0.441

AC:

17443

AN:

39518

South Asian (SAS)

AF:

0.395

AC:

33651

AN:

85164

European-Finnish (FIN)

AF:

0.206

AC:

10917

AN:

53098

Middle Eastern (MID)

AF:

0.249

AC:

1418

AN:

5706

European-Non Finnish (NFE)

AF:

0.173

AC:

191515

AN:

1106004

Other (OTH)

AF:

0.211

AC:

12619

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

13757

27514

41271

55028

68785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7118

14236

21354

28472

35590

<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:

0.197

AC:

29920

AN:

152044

Hom.:

3373

Cov.:

AF XY:

0.202

AC XY:

15047

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.167

AC:

6921

AN:

41494

American (AMR)

AF:

0.249

AC:

3807

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

682

AN:

3466

East Asian (EAS)

AF:

0.456

AC:

2339

AN:

5128

South Asian (SAS)

AF:

0.406

AC:

1949

AN:

4806

European-Finnish (FIN)

AF:

0.194

AC:

2052

AN:

10586

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11579

AN:

67970

Other (OTH)

AF:

0.212

AC:

447

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1205

2409

3614

4818

6023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.188

Hom.:

6735

Bravo

AF:

0.199

TwinsUK

AF:

0.181

AC:

671

ALSPAC

AF:

0.172

AC:

663

ESP6500AA

AF:

0.172

AC:

758

ESP6500EA

AF:

0.170

AC:

1458

ExAC

AF:

0.238

AC:

28836

Asia WGS

AF:

0.379

AC:

1316

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.7

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0018

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.00015

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

N;.

PhyloP100

-0.21

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.92

N;.

REVEL

Benign

0.068

Sift

Benign

0.080

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.11

B;.

Vest4

0.075

MPC

0.28

ClinPred

0.0076

GERP RS

-0.54

PromoterAI

-0.13

Neutral

(source)

Varity_R

0.012

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