Genetic Variant SLC25A15:p.Arg61His (chr13-40799183-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_014252.4(SLC25A15):c.182G>A(p.Arg61His) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,614,208 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts 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. R61C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 14 hom. )

Consequence

SLC25A15
NM_014252.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 5.52

Publications

7 publications found

Variant links:

Genes affected

SLC25A15 (HGNC:10985): (solute carrier family 25 member 15) This gene is a member of the mitochondrial carrier family. The encoded protein transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix. The protein is an essential component of the urea cycle, and functions in ammonium detoxification and biosynthesis of the amino acid arginine. Mutations in this gene result in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. There is a pseudogene of this locus on the Y chromosome.[provided by RefSeq, May 2009]

SLC25A15 links:

SUGT1P3 (HGNC:):

SUGT1P3 links:

TPTE2P5 (HGNC:42356): (TPTE2 pseudogene 5)

TPTE2P5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a repeat Solcar 1 (size 84) in uniprot entity ORNT1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_014252.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.10098 (below the threshold of 3.09). Trascript score misZ: 1.3225 (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine translocase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.018633276).

BP6

Variant 13-40799183-G-A is Benign according to our data. Variant chr13-40799183-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203939.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00283 (431/152316) while in subpopulation NFE AF = 0.0051 (347/68034). AF 95% confidence interval is 0.00466. There are 1 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A15	NM_014252.4	MANE Select	c.182G>A	p.Arg61His	missense	Exon 3 of 7	NP_055067.1	Q9Y619
TPTE2P5	NR_038258.1		n.2164C>T		non_coding_transcript_exon	Exon 8 of 8
TPTE2P5	NR_038259.1		n.1993C>T		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A15	ENST00000338625.9	TSL:1 MANE Select	c.182G>A	p.Arg61His	missense	Exon 3 of 7	ENSP00000342267.4	Q9Y619
SLC25A15	ENST00000707033.1		c.182G>A	p.Arg61His	missense	Exon 3 of 7	ENSP00000516711.1	Q9Y619
SLC25A15	ENST00000899653.1		c.182G>A	p.Arg61His	missense	Exon 3 of 7	ENSP00000569712.1

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

431

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00510

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00235

AC:

591

AN:

251426

AF XY:

0.00227

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00458

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00440

AC:

6426

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

3108

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00121

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000674

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00545

AC:

6065

AN:

1112010

Other (OTH)

AF:

0.00397

AC:

240

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

422

844

1267

1689

2111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<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:

0.00283

AC:

431

AN:

152316

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41558

American (AMR)

AF:

0.00118

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00510

AC:

347

AN:

68034

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00425

Hom.:

Bravo

AF:

0.00289

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00231

AC:

280

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00421

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (3)

Intellectual disability (1)

SLC25A15-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.6

PhyloP100

5.5

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.41

Sift

Benign

0.036

Sift4G

Uncertain

0.026

Polyphen

0.15

Vest4

0.66

MVP

0.84

MPC

0.14

ClinPred

0.070

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.83

Mutation Taster

=87/13

polymorphism

(source)

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

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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