14-92577459-A-C

Variant names:

• chr14-92577459-A-C
• rs149690430
• NM_024832.5:c.349A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024832.5(RIN3):​c.349A>C​(p.Ile117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 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. I117V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIN3 NM_024832.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.880
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN3	NM_024832.5	MANE Select	c.349A>C	p.Ile117Leu	missense	Exon 3 of 10	NP_079108.3
	RIN3	NM_001319987.2		c.124A>C	p.Ile42Leu	missense	Exon 2 of 9	NP_001306916.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN3	ENST00000216487.12	TSL:1 MANE Select	c.349A>C	p.Ile117Leu	missense	Exon 3 of 10	ENSP00000216487.7	Q8TB24-1
	RIN3	ENST00000555589.5	TSL:1	n.349A>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000450682.1	G3V2I7
	RIN3	ENST00000863459.1		c.349A>C	p.Ile117Leu	missense	Exon 3 of 9	ENSP00000533518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459646 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726294

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110340

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.88
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.20	B
Vest4		0.45
MutPred		0.60		Gain of disorder (P = 0.0957)
MVP		0.67
MPC		0.26
ClinPred		0.41	T
GERP RS		1.2
Varity_R		0.099
gMVP		0.59
Mutation Taster		=91/9	polymorphism

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: rs149690430; hg19: chr14-93043804;