14-92652887-G-C

Variant names:

• chr14-92652887-G-C
• rs12434929
• NM_024832.5:c.1838G>C

Variant summary

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

The NM_024832.5(RIN3):​c.1838G>C​(p.Gly613Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,034 control chromosomes in the GnomAD database, including 715 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (355 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (360 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011604726).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5	c.1838G>C	p.Gly613Ala	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3
RIN3	NM_001319987.2	c.1613G>C	p.Gly538Ala	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	c.1838G>C	p.Gly613Ala	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6142 AN: 152174 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00632

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0153 AC: 3833 AN: 251148 Hom.: 153 AF XY: 0.0128 AC XY: 1744 AN XY: 135784

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00752

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00935 AC: 13669 AN: 1461742 Hom.: 360 Cov.: 36 AF XY: 0.00879 AC XY: 6393 AN XY: 727176

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.00823

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00497

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00595

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0406 AC: 6178 AN: 152292 Hom.: 355 Cov.: 32 AF XY: 0.0398 AC XY: 2963 AN XY: 74470

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.00632

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0112 Hom.: 22

Bravo AF: 0.0438

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.118 AC: 521

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.0182 AC: 2215

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.00080	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.070	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.043
Sift	Benign	0.81	T;.
Sift4G	Benign	0.92	T;T
Polyphen		0.012	B;.
Vest4		0.026
MPC		0.29
ClinPred		0.00052	T
GERP RS		1.3
Varity_R		0.020
gMVP		0.14

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: rs12434929; hg19: chr14-93119232;