Genetic Variant RNFT2:p.Ala225Val (chr12-116766860-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001382266.1(RNFT2):c.674C>T(p.Ala225Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000501 in 1,598,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

RNFT2
NM_001382266.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Variant links:

Genes affected

RNFT2 (HGNC:25905): (ring finger protein, transmembrane 2) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in positive regulation of ERAD pathway and protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNFT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045671284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNFT2	NM_001382266.1 link	c.674C>T	p.Ala225Val	missense_variant	Exon 6 of 11	ENST00000257575.9	NP_001369195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNFT2	ENST00000257575.9 link	c.674C>T	p.Ala225Val	missense_variant	Exon 6 of 11	5	NM_001382266.1	ENSP00000257575.4		Q96EX2-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000885

AC:

AN:

225922

Hom.:

AF XY:

0.0000909

AC XY:

AN XY:

121024

show subpopulations

Gnomad AFR exome

AF:

0.0000702

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000594

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000199

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1445996

Hom.:

Cov.:

AF XY:

0.0000655

AC XY:

AN XY:

717572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000709

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000510

Gnomad4 SAS exome

AF:

0.000481

Gnomad4 FIN exome

AF:

0.0000571

Gnomad4 NFE exome

AF:

0.0000163

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674C>T (p.A225V) alteration is located in exon 6 (coding exon 5) of the RNFT2 gene. This alteration results from a C to T substitution at nucleotide position 674, causing the alanine (A) at amino acid position 225 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

T;T;.;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.055

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.86

.;D;D;D;D

M_CAP

Benign

0.0072

MetaRNN

Benign

0.046

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.85

N;N;N;.;N

REVEL

Benign

0.019

Sift

Benign

0.27

T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0010

B;B;.;.;.

Vest4

0.26

MVP

0.043

MPC

0.23

ClinPred

0.025

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.039

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over