14-92652478-C-T

Variant names:

• chr14-92652478-C-T
• rs74074812
• NM_024832.5:c.1429C>T

Variant summary

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

The NM_024832.5(RIN3):​c.1429C>T​(p.Pro477Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,614,078 control chromosomes in the GnomAD database, including 807 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (412 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (395 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58

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=0.0015961528).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN3	NM_024832.5	c.1429C>T	p.Pro477Ser	missense_variant	Exon 6 of 10	ENST00000216487.12	NP_079108.3
RIN3	NM_001319987.2	c.1204C>T	p.Pro402Ser	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.1429C>T	p.Pro477Ser	missense_variant	Exon 6 of 10	1	NM_024832.5	ENSP00000216487.7

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6090 AN: 152112 Hom.: 412 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0102 AC: 2555 AN: 251272 Hom.: 164 AF XY: 0.00743 AC XY: 1009 AN XY: 135822

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00399 AC: 5830 AN: 1461848 Hom.: 395 Cov.: 36 AF XY: 0.00341 AC XY: 2481 AN XY: 727222

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.00680

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00810

GnomAD4 genome AF: 0.0401 AC: 6102 AN: 152230 Hom.: 412 Cov.: 32 AF XY: 0.0381 AC XY: 2839 AN XY: 74442

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.00532 Hom.: 76

Bravo AF: 0.0454

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.133 AC: 585

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0131 AC: 1588

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0076	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.058
Sift	Benign	0.19	T;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.47	P;.
Vest4		0.33
MPC		0.37
ClinPred		0.0041	T
GERP RS		3.6
Varity_R		0.031
gMVP		0.16

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: rs74074812; hg19: chr14-93118823; COSMIC: COSV99076133; COSMIC: COSV99076133;