chr13-40799183-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_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).

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

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:

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

TPTE2P5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a chain Mitochondrial ornithine transporter 1 (size 300) in uniprot entity ORNT1_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_014252.4

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 id is 203939.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr13-40799183-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A15	NM_014252.4 link	c.182G>A	p.Arg61His	missense_variant	Exon 3 of 7	ENST00000338625.9	NP_055067.1	Q9Y619
TPTE2P5	NR_038258.1 link	n.2164C>T		non_coding_transcript_exon_variant	Exon 8 of 8
TPTE2P5	NR_038259.1 link	n.1993C>T		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A15	ENST00000338625.9 link	c.182G>A	p.Arg61His	missense_variant	Exon 3 of 7	1	NM_014252.4	ENSP00000342267.4		Q9Y619

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

GnomAD3 exomes

AF:

0.00235

AC:

591

AN:

251426

Hom.:

AF XY:

0.00227

AC XY:

309

AN XY:

135908

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 SAS 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

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000674

Gnomad4 NFE exome

AF:

0.00545

Gnomad4 OTH exome

AF:

0.00397

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152316

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00510

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00427

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC25A15 p.Arg61His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs34615430), ClinVar (classified as a VUS by GeneDx, EGL Genetics and Illumina and as likely benign by Invitae for hyperornithinemia-hyperammonemia-homocitrullinemia syndrome) and LOVD 3.0 (reported as likely benign). The variant was identified in control databases in 663 of 282814 chromosomes at a frequency of 0.002344 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 582 of 129132 chromosomes (freq: 0.004507), Other in 18 of 7228 chromosomes (freq: 0.00249), African in 23 of 24958 chromosomes (freq: 0.000922), Latino in 30 of 35438 chromosomes (freq: 0.000847) and European (Finnish) in 10 of 25122 chromosomes (freq: 0.000398); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg61 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC25A15: BS2 -

Apr 03, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R61H variant in the SLC25A15 gene has been reported as a rare variant identified in 12 patients with multiple sclerosis, but was also observed in 10 healthy controls (Traboulsee et al., 2017). The R61H variant is observed in 577/126660 (0.45%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R61H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R61H as a variant of uncertain significance. -

Sep 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Apr 21, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Uncertain:1Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLC25A15-related disorder

Benign:1

Feb 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

D;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.41

Sift

Benign

0.036

D;D

Sift4G

Uncertain

0.026

D;T

Polyphen

0.15

B;.

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

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