Genetic Variant NM_024832.5:c.1280G>A (chr14-92652329-G-A) – 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.1280G>A(p.Arg427Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,604,332 control chromosomes in the GnomAD database, including 1,178 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.048 ( 549 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 629 hom. )

Consequence

RIN3
NM_024832.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.773

Publications

7 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=0.0012609661).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5 link	c.1280G>A	p.Arg427Gln	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3	Q8TB24-1Q6NSK7Q86U22
RIN3	NM_001319987.2 link	c.1055G>A	p.Arg352Gln	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.1280G>A	p.Arg427Gln	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7		Q8TB24-1

Frequencies

GnomAD3 genomes

AF:

0.0476

AC:

7244

AN:

152044

Hom.:

549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0293

Gnomad SAS

AF:

0.0447

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.0415

GnomAD2 exomes

AF:

0.0200

AC:

4888

AN:

243820

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.00710

Gnomad ASJ exome

AF:

0.00557

Gnomad EAS exome

AF:

0.0348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000865

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00819

AC:

11892

AN:

1452170

Hom.:

629

Cov.:

AF XY:

0.00857

AC XY:

6178

AN XY:

721232

show subpopulations

African (AFR)

AF:

0.160

AC:

5350

AN:

33342

American (AMR)

AF:

0.00861

AC:

380

AN:

44130

Ashkenazi Jewish (ASJ)

AF:

0.00496

AC:

126

AN:

25378

East Asian (EAS)

AF:

0.0240

AC:

948

AN:

39520

South Asian (SAS)

AF:

0.0401

AC:

3416

AN:

85136

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53088

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000518

AC:

573

AN:

1105992

Other (OTH)

AF:

0.0172

AC:

1030

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

719

1437

2156

2874

3593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.0477

AC:

7251

AN:

152162

Hom.:

549

Cov.:

AF XY:

0.0463

AC XY:

3441

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.155

AC:

6439

AN:

41482

American (AMR)

AF:

0.0183

AC:

280

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0288

AC:

148

AN:

5144

South Asian (SAS)

AF:

0.0441

AC:

212

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68020

Other (OTH)

AF:

0.0411

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

318

637

955

1274

1592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0232

Hom.:

191

Bravo

AF:

0.0523

ESP6500AA

AF:

0.146

AC:

643

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0230

AC:

2790

Asia WGS

AF:

0.0590

AC:

203

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0070

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.00065

T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.7

N;.

PhyloP100

-0.77

PrimateAI

Benign

0.16

PROVEAN

Benign

0.15

N;.

REVEL

Benign

0.011

Sift

Benign

0.80

T;.

Sift4G

Benign

0.76

T;T

Polyphen

0.041

B;.

Vest4

0.048

MPC

0.31

ClinPred

0.0065

GERP RS

-6.8

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.016

gMVP

0.091

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