NM_024832.5:c.1274C>T

Variant names:

• chr14-92652323-C-T
• rs3742717
• NM_024832.5:c.1274C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 0.20 (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
• Publications: 31 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024832.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN3	NM_024832.5	MANE Select	c.1274C>T	p.Thr425Met	missense	Exon 6 of 10	NP_079108.3
	RIN3	NM_001319987.2		c.1049C>T	p.Thr350Met	missense	Exon 5 of 9	NP_001306916.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN3	ENST00000216487.12	TSL:1 MANE Select	c.1274C>T	p.Thr425Met	missense	Exon 6 of 10	ENSP00000216487.7
	RIN3	ENST00000555589.5	TSL:1	n.*721C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000450682.1
	RIN3	ENST00000555589.5	TSL:1	n.*721C>T		3_prime_UTR	Exon 5 of 9	ENSP00000450682.1

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

GnomAD2 exomes AF: 0.241 AC: 58879 AN: 244098 AF XY: 0.244

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 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

African (AFR) AF: 0.172 AC: 5735 AN: 33274

American (AMR) AF: 0.272 AC: 11942 AN: 43912

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4647 AN: 25428

East Asian (EAS) AF: 0.441 AC: 17443 AN: 39518

South Asian (SAS) AF: 0.395 AC: 33651 AN: 85164

European-Finnish (FIN) AF: 0.206 AC: 10917 AN: 53098

Middle Eastern (MID) AF: 0.249 AC: 1418 AN: 5706

European-Non Finnish (NFE) AF: 0.173 AC: 191515 AN: 1106004

Other (OTH) AF: 0.211 AC: 12619 AN: 59828

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

African (AFR) AF: 0.167 AC: 6921 AN: 41494

American (AMR) AF: 0.249 AC: 3807 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 682 AN: 3466

East Asian (EAS) AF: 0.456 AC: 2339 AN: 5128

South Asian (SAS) AF: 0.406 AC: 1949 AN: 4806

European-Finnish (FIN) AF: 0.194 AC: 2052 AN: 10586

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11579 AN: 67970

Other (OTH) AF: 0.212 AC: 447 AN: 2110

Alfa AF: 0.188 Hom.: 6735

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 v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.21
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.068
Sift	Benign	0.080	T
Sift4G	Benign	0.12	T
Polyphen		0.11	B
Vest4		0.075
MPC		0.28
ClinPred		0.0076	T
GERP RS		-0.54
PromoterAI		-0.13	Neutral
Varity_R		0.012
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3742717; hg19: chr14-93118668; COSMIC: COSV53644905; COSMIC: COSV53644905;