14-92652323-C-T

Position:

• chr14-92652323-C-T

Variant summary

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

The NM_024832.5(RIN3):​c.1274C>T​(p.Thr425Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,603,976 control chromosomes in the GnomAD database, including 36,207 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. T425I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3373 hom., cov: 30)
  • Exomes 𝑓: 0.20 (32834 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211

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=1.4650822E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN3	NM_024832.5	c.1274C>T	p.Thr425Met	missense_variant	6/10	ENST00000216487.12	NP_079108.3
RIN3	NM_001319987.2	c.1049C>T	p.Thr350Met	missense_variant	5/9		NP_001306916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN3	ENST00000216487.12	c.1274C>T	p.Thr425Met	missense_variant	6/10	1	NM_024832.5	ENSP00000216487.7

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29882 AN: 151926 Hom.: 3365 Cov.: 30

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.241 AC: 58879 AN: 244098 Hom.: 8264 AF XY: 0.244 AC XY: 32215 AN XY: 131856

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.200 AC: 289887 AN: 1451932 Hom.: 32834 Cov.: 49 AF XY: 0.205 AC XY: 147516 AN XY: 721118

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.197 AC: 29920 AN: 152044 Hom.: 3373 Cov.: 30 AF XY: 0.202 AC XY: 15047 AN XY: 74324

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.456

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.212

Alfa AF: 0.186 Hom.: 4589

Bravo AF: 0.199

TwinsUK AF: 0.181 AC: 671

ALSPAC AF: 0.172 AC: 663

ESP6500AA AF: 0.172 AC: 758

ESP6500EA AF: 0.170 AC: 1458

ExAC AF: 0.238 AC: 28836

Asia WGS AF: 0.379 AC: 1316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.7
DANN	Benign	0.92
DEOGEN2	Benign	0.0018	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.00015	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.92	N;.
REVEL	Benign	0.068
Sift	Benign	0.080	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.11	B;.
Vest4		0.075
MPC		0.28
ClinPred		0.0076	T
GERP RS		-0.54
Varity_R		0.012
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: rs3742717; hg19: chr14-93118668; COSMIC: COSV53644905; COSMIC: COSV53644905;