rs34615430

chr13-40799183-G-Achr13-40799183-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 5.52

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]

TPTE2P5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a repeat Solcar 1 (size 84) in uniprot entity ORNT1_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) 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: {Uncertain_significance=3, Likely_benign=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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A15	NM_014252.4	c.182G>A	p.Arg61His	missense_variant	3/7	ENST00000338625.9
TPTE2P5	NR_038259.1	n.1993C>T		non_coding_transcript_exon_variant	6/6
TPTE2P5	NR_038258.1	n.2164C>T		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A15	ENST00000338625.9	c.182G>A	p.Arg61His	missense_variant	3/7	1	NM_014252.4	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152198 Hom.: 1 Cov.: 32

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.: 0 AF XY: 0.00227 AC XY: 309 AN XY: 135908

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.: 14 Cov.: 35 AF XY: 0.00427 AC XY: 3108 AN XY: 727248

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.: 1 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74476

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.: 6

Bravo AF: 0.00289

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00231 AC: 280

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SLC25A15: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2018	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. -

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -

SLC25A15-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2022

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

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
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	T
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

Other links and lift over

dbSNP: rs34615430; hg19: chr13-41373319;