NM_016492.5:c.52C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18I) has been classified as Uncertain significance.

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

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

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

BP6

Variant 17-8288840-C-T is Benign according to our data. Variant chr17-8288840-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190841.

BS2

High AC in GnomAd4 at 100 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016492.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RANGRF	NM_016492.5	MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 1 of 5	NP_057576.2
RANGRF	NM_001177802.2		c.52C>T	p.Leu18Phe	missense	Exon 1 of 3	NP_001171273.1	Q9HD47-3
RANGRF	NM_001177801.2		c.52C>T	p.Leu18Phe	missense	Exon 1 of 4	NP_001171272.1	Q9HD47-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RANGRF	ENST00000226105.11	TSL:1 MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 1 of 5	ENSP00000226105.6	Q9HD47-1
RANGRF	ENST00000439238.3	TSL:1	c.52C>T	p.Leu18Phe	missense	Exon 1 of 3	ENSP00000413190.3	Q9HD47-3
RANGRF	ENST00000407006.8	TSL:1	c.52C>T	p.Leu18Phe	missense	Exon 1 of 4	ENSP00000383940.4	Q9HD47-2

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

GnomAD2 exomes

AF:

0.000590

AC:

148

AN:

250876

AF XY:

0.000567

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 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

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00127

AC:

1415

AN:

1112002

Other (OTH)

AF:

0.00124

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000656

AC:

100

AN:

152352

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41594

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000795

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiac arrhythmia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.084

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.69

M_CAP

Benign

0.062

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.47

Sift

Benign

0.099

Sift4G

Benign

0.18

Polyphen

0.035

Vest4

0.18

MVP

0.74

MPC

0.32

ClinPred

0.039

GERP RS

4.4

PromoterAI

0.44

Neutral

(source)

Varity_R

0.18

gMVP

0.54

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over