14-92651693-A-G

Position:

• chr14-92651693-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024832.5(RIN3):​c.644A>G​(p.His215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,544 control chromosomes in the GnomAD database, including 232,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H215L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (19541 hom., cov: 30)
  • Exomes 𝑓: 0.54 (212818 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8135715E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN3	NM_024832.5	c.644A>G	p.His215Arg	missense_variant	6/10	ENST00000216487.12	NP_079108.3
RIN3	NM_001319987.2	c.419A>G	p.His140Arg	missense_variant	5/9		NP_001306916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN3	ENST00000216487.12	c.644A>G	p.His215Arg	missense_variant	6/10	1	NM_024832.5	ENSP00000216487.7

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75743 AN: 151796 Hom.: 19526 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.528

GnomAD3 exomes AF: 0.483 AC: 121477 AN: 251366 Hom.: 30759 AF XY: 0.490 AC XY: 66512 AN XY: 135852

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.464

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.535 AC: 782416 AN: 1461630 Hom.: 212818 Cov.: 56 AF XY: 0.535 AC XY: 389031 AN XY: 727120

Gnomad4 AFR exome AF: 0.436

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.466

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.530

GnomAD4 genome AF: 0.499 AC: 75799 AN: 151914 Hom.: 19541 Cov.: 30 AF XY: 0.492 AC XY: 36501 AN XY: 74228

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.459

Gnomad4 NFE AF: 0.565

Gnomad4 OTH AF: 0.526

Alfa AF: 0.539 Hom.: 35206

Bravo AF: 0.497

TwinsUK AF: 0.541 AC: 2006

ALSPAC AF: 0.572 AC: 2203

ESP6500AA AF: 0.456 AC: 2011

ESP6500EA AF: 0.570 AC: 4902

ExAC AF: 0.487 AC: 59189

Asia WGS AF: 0.413 AC: 1436 AN: 3478

EpiCase AF: 0.574

EpiControl AF: 0.574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.16
DANN	Benign	0.76
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.000028	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.018
Sift	Benign	0.22	T;.
Sift4G	Benign	0.70	T;T
Polyphen		0.0	B;.
Vest4		0.14
MPC		0.32
ClinPred		0.0093	T
GERP RS		-5.5
Varity_R		0.029
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs3829947; hg19: chr14-93118038; COSMIC: COSV53644654; COSMIC: COSV53644654;