dbSNP rs3829947: RIN3:p.His215Pro (chr14-92651693-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024832.5(RIN3):c.644A>C(p.His215Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. H215Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RIN3
NM_024832.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.308

Publications

29 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.110746324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5 link	c.644A>C	p.His215Pro	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3	Q8TB24-1Q6NSK7Q86U22
RIN3	NM_001319987.2 link	c.419A>C	p.His140Pro	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.644A>C	p.His215Pro	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7		Q8TB24-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000659

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41306

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

47198

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.41

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.0029

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

-0.31

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.77

N;.

REVEL

Benign

0.028

Sift

Benign

0.060

T;.

Sift4G

Benign

0.40

T;T

Polyphen

0.0010

B;.

Vest4

0.23

MutPred

0.15

Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);

MVP

0.29

MPC

0.41

ClinPred

0.057

GERP RS

-5.5

Varity_R

0.054

gMVP

0.41

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over