14-92651693-A-G

Variant names:

• chr14-92651693-A-G
• rs3829947
• NM_024832.5:c.644A>G

Variant summary

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

The NM_024832.5(RIN3):​c.644A>G​(p.His215Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,544 control chromosomes in the GnomAD database, including 232,359 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. H215Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.50 (19541 hom., cov: 30)
  • Exomes 𝑓: 0.54 (212818 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308
• Publications: 29 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=2.8135715E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.56 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.644A>G	p.His215Arg	missense	Exon 6 of 10	NP_079108.3
	RIN3	NM_001319987.2		c.419A>G	p.His140Arg	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.644A>G	p.His215Arg	missense	Exon 6 of 10	ENSP00000216487.7
	RIN3	ENST00000555589.5	TSL:1	n.*91A>G		non_coding_transcript_exon	Exon 5 of 9	ENSP00000450682.1
	RIN3	ENST00000555589.5	TSL:1	n.*91A>G		3_prime_UTR	Exon 5 of 9	ENSP00000450682.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75743 AN: 151796 Hom.: 19526 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.528

GnomAD2 exomes AF: 0.483 AC: 121477 AN: 251366 AF XY: 0.490

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.535 AC: 782416 AN: 1461630 Hom.: 212818 Cov.: 56 AF XY: 0.535 AC XY: 389031 AN XY: 727120

African (AFR) AF: 0.436 AC: 14579 AN: 33472

American (AMR) AF: 0.369 AC: 16509 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14641 AN: 26128

East Asian (EAS) AF: 0.270 AC: 10729 AN: 39700

South Asian (SAS) AF: 0.466 AC: 40230 AN: 86256

European-Finnish (FIN) AF: 0.465 AC: 24857 AN: 53414

Middle Eastern (MID) AF: 0.567 AC: 3271 AN: 5764

European-Non Finnish (NFE) AF: 0.563 AC: 625614 AN: 1111796

Other (OTH) AF: 0.530 AC: 31986 AN: 60388

GnomAD4 genome AF: 0.499 AC: 75799 AN: 151914 Hom.: 19541 Cov.: 30 AF XY: 0.492 AC XY: 36501 AN XY: 74228

African (AFR) AF: 0.444 AC: 18375 AN: 41406

American (AMR) AF: 0.444 AC: 6789 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1886 AN: 3468

East Asian (EAS) AF: 0.274 AC: 1406 AN: 5138

South Asian (SAS) AF: 0.456 AC: 2195 AN: 4812

European-Finnish (FIN) AF: 0.459 AC: 4849 AN: 10560

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38364 AN: 67940

Other (OTH) AF: 0.526 AC: 1108 AN: 2106

Alfa AF: 0.536 Hom.: 47198

Bravo AF: 0.497

TwinsUK AF: 0.541 AC: 2006

ALSPAC AF: 0.572 AC: 2203

ESP6500AA AF: 0.456 AC: 2011

ESP6500EA AF: 0.570 AC: 4902

ExAC AF: 0.487 AC: 59189

Asia WGS AF: 0.413 AC: 1436 AN: 3478

EpiCase AF: 0.574

EpiControl AF: 0.574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.16
DANN	Benign	0.76
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N
PhyloP100		-0.31
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.018
Sift	Benign	0.22	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.32
ClinPred		0.0093	T
GERP RS		-5.5
Varity_R		0.029
gMVP		0.34
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: rs3829947; hg19: chr14-93118038; COSMIC: COSV53644654; COSMIC: COSV53644654;