Variant 17-8288855-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000226105.11(RANGRF):c.67A>G(p.Ile23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

RANGRF
ENST00000226105.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Variant links:

Genes affected

RANGRF (HGNC:17679): (RAN guanine nucleotide release factor) This gene encodes a protein that has been shown to function as a guanine nucleotide release factor in mouse and to regulate the expression and function of the Nav1.5 cardiac sodium channel in human. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RANGRF links:

SLC25A35 (HGNC:31921): (solute carrier family 25 member 35) SLC25A35 belongs to the SLC25 family of mitochondrial carrier proteins (Haitina et al., 2006 [PubMed 16949250]).[supplied by OMIM, Mar 2008]

SLC25A35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.295377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANGRF	NM_016492.5 linkuse as main transcript	c.67A>G	p.Ile23Val	missense_variant	1/5	ENST00000226105.11	NP_057576.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANGRF	ENST00000226105.11 linkuse as main transcript	c.67A>G	p.Ile23Val	missense_variant	1/5	1	NM_016492.5	ENSP00000226105	P1	Q9HD47-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250688

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the RANGRF protein (p.Ile23Val). This variant is present in population databases (rs371469933, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RANGRF-related conditions. ClinVar contains an entry for this variant (Variation ID: 2142264). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.029

T;.;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.50

T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

0.98

N;N;N;N;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

0.040

N;N;.;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;.;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.084

B;.;B;P

Vest4

0.23

MVP

0.66

MPC

0.26

ClinPred

0.14

GERP RS

1.8

Varity_R

0.034

gMVP

0.20

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