NM_024832.5:c.1280G>A

Variant names:

• chr14-92652329-G-A
• rs74074811
• NM_024832.5:c.1280G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024832.5(RIN3):​c.1280G>A​(p.Arg427Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,604,332 control chromosomes in the GnomAD database, including 1,178 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R427W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.048 (549 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (629 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.773
• Publications: 7 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=0.0012609661).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 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.1280G>A	p.Arg427Gln	missense	Exon 6 of 10	NP_079108.3
	RIN3	NM_001319987.2		c.1055G>A	p.Arg352Gln	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.1280G>A	p.Arg427Gln	missense	Exon 6 of 10	ENSP00000216487.7
	RIN3	ENST00000555589.5	TSL:1	n.*727G>A		non_coding_transcript_exon	Exon 5 of 9	ENSP00000450682.1
	RIN3	ENST00000555589.5	TSL:1	n.*727G>A		3_prime_UTR	Exon 5 of 9	ENSP00000450682.1

Frequencies

GnomAD3 genomes AF: 0.0476 AC: 7244 AN: 152044 Hom.: 549 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0200 AC: 4888 AN: 243820 AF XY: 0.0182

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.00710

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.0348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00819 AC: 11892 AN: 1452170 Hom.: 629 Cov.: 36 AF XY: 0.00857 AC XY: 6178 AN XY: 721232

African (AFR) AF: 0.160 AC: 5350 AN: 33342

American (AMR) AF: 0.00861 AC: 380 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.00496 AC: 126 AN: 25378

East Asian (EAS) AF: 0.0240 AC: 948 AN: 39520

South Asian (SAS) AF: 0.0401 AC: 3416 AN: 85136

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53088

Middle Eastern (MID) AF: 0.0119 AC: 68 AN: 5708

European-Non Finnish (NFE) AF: 0.000518 AC: 573 AN: 1105992

Other (OTH) AF: 0.0172 AC: 1030 AN: 59876

GnomAD4 genome AF: 0.0477 AC: 7251 AN: 152162 Hom.: 549 Cov.: 32 AF XY: 0.0463 AC XY: 3441 AN XY: 74372

African (AFR) AF: 0.155 AC: 6439 AN: 41482

American (AMR) AF: 0.0183 AC: 280 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.0288 AC: 148 AN: 5144

South Asian (SAS) AF: 0.0441 AC: 212 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68020

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0232 Hom.: 191

Bravo AF: 0.0523

ESP6500AA AF: 0.146 AC: 643

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0230 AC: 2790

Asia WGS AF: 0.0590 AC: 203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0070
DANN	Benign	0.63
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.7	N
PhyloP100		-0.77
PrimateAI	Benign	0.16	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.011
Sift	Benign	0.80	T
Sift4G	Benign	0.76	T
Polyphen		0.041	B
Vest4		0.048
MPC		0.31
ClinPred		0.0065	T
GERP RS		-6.8
PromoterAI		-0.059	Neutral
Varity_R		0.016
gMVP		0.091
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: rs74074811; hg19: chr14-93118674; COSMIC: COSV53649228; COSMIC: COSV53649228;