rs74074811

chr14-92652329-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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 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

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=0.0012609661).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN3	NM_024832.5	c.1280G>A	p.Arg427Gln	missense_variant	6/10	ENST00000216487.12
RIN3	NM_001319987.2	c.1055G>A	p.Arg352Gln	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN3	ENST00000216487.12	c.1280G>A	p.Arg427Gln	missense_variant	6/10	1	NM_024832.5	P2
RIN3	ENST00000555589.5	c.*727G>A		3_prime_UTR_variant, NMD_transcript_variant	5/9	1
RIN3	ENST00000620541.4	c.1064G>A	p.Arg355Gln	missense_variant	7/11	5		A2
RIN3	ENST00000418924.6	n.1179G>A		non_coding_transcript_exon_variant	5/9	2

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

GnomAD3 exomes AF: 0.0200 AC: 4888 AN: 243820 Hom.: 247 AF XY: 0.0182 AC XY: 2391 AN XY: 131596

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 SAS exome AF: 0.0440

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

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.00861

Gnomad4 ASJ exome AF: 0.00496

Gnomad4 EAS exome AF: 0.0240

Gnomad4 SAS exome AF: 0.0401

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000518

Gnomad4 OTH exome AF: 0.0172

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

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.0441

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0201 Hom.: 112

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 v4.3

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;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.16	T
PROVEAN	Benign	0.15	N;.
REVEL	Benign	0.011
Sift	Benign	0.80	T;.
Sift4G	Benign	0.76	T;T
Polyphen		0.041	B;.
Vest4		0.048
MPC		0.31
ClinPred		0.0065	T
GERP RS		-6.8
Varity_R		0.016
gMVP		0.091

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: rs74074811; hg19: chr14-93118674; COSMIC: COSV53649228; COSMIC: COSV53649228;