chr17-8288840-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016492.5(RANGRF):c.52C>T(p.Leu18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

RANGRF
NM_016492.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.50

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.085507065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANGRF	NM_016492.5 link	c.52C>T	p.Leu18Phe	missense_variant	Exon 1 of 5	ENST00000226105.11	NP_057576.2	Q9HD47-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANGRF	ENST00000226105.11 link	c.52C>T	p.Leu18Phe	missense_variant	Exon 1 of 5	1	NM_016492.5	ENSP00000226105.6		Q9HD47-1

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000590

AC:

148

AN:

250876

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.000437

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.00106

AC:

1546

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

725

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000599

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000656

AC:

100

AN:

152352

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000850

Hom.:

Bravo

AF:

0.000567

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 30, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with hypertrophic cardiomyopathy (HCM) in published literature (Ashraf et al., 2023); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 36582594) -

Cardiac arrhythmia

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 18 of the RANGRF protein (p.Leu18Phe). This variant is present in population databases (rs150856064, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 190841). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified

Benign:1

Jan 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.084

T;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.086

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.1

L;L;L;L

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

D;D;.;N

REVEL

Uncertain

0.47

Sift

Benign

0.099

T;T;.;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.035

B;.;B;B

Vest4

0.18

MVP

0.74

MPC

0.32

ClinPred

0.039

GERP RS

4.4

Varity_R

0.18

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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