rs202247803

Positions:

chr13-40807393-TTTC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_014252.4(SLC25A15):c.562_564del(p.Phe188del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SLC25A15
NM_014252.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.92

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:):

TPTE2P5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_014252.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 13-40807393-TTTC-T is Pathogenic according to our data. Variant chr13-40807393-TTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 5992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-40807393-TTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC25A15	NM_014252.4 linkuse as main transcript	c.562_564del	p.Phe188del	inframe_deletion	5/7	ENST00000338625.9	NP_055067.1
TPTE2P5	NR_038259.1 linkuse as main transcript	n.452-6672_452-6670del		intron_variant, non_coding_transcript_variant
TPTE2P5	NR_038258.1 linkuse as main transcript	n.623-6672_623-6670del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A15	ENST00000338625.9 linkuse as main transcript	c.562_564del	p.Phe188del	inframe_deletion	5/7	1	NM_014252.4	ENSP00000342267	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251490

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461864

Hom.:

AF XY:

0.0000330

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	May 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This variant, c.562_564del, results in the deletion of 1 amino acid(s) of the SLC25A15 protein (p.Phe188del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs747270765, gnomAD 0.01%). This variant has been observed in individual(s) with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) (PMID: 10369256, 23247599). It is commonly reported in individuals of French ancestry (PMID: 10369256, 23247599). ClinVar contains an entry for this variant (Variation ID: 5992). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC25A15 function (PMID: 10369256, 12807890, 23430880). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2024	Variant summary: SLC25A15 c.562_564delTTC (p.Phe188del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 6.4e-05 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC25A15 causing Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome, allowing no conclusion about variant significance. c.562_564delTTC has been reported in the literature in multiple homozygous individuals of French ancestry affected with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (e.g. Debray_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significantly reduced ORNT1 transporting activity (e.g. Camacho_2006). The following publications have been ascertained in the context of this evaluation (PMID: 18978333, 10369256). ClinVar contains an entry for this variant (Variation ID: 5992). Based on the evidence outlined above, the variant was classified as pathogenic. -

SLC25A15-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

The SLC25A15 c.562_564delTTC variant is predicted to result in an in-frame deletion (p.Phe188del). This variant has been reported as causative for hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome. It is a common variant in French Canadian and northern Saskatchewan populations (Camacho et al. 1999. PubMed ID: 10369256; Sokoro et al. 2010. PubMed ID: 20574716). Functional studies have shown that this variant results in a loss in protein activity (Camacho et al. 1999. PubMed ID: 10369256). This variant is often designated as F188Δ in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2022

Published functional studies demonstrate a damaging effect impairing stability and/or targeting transporter function (Camacho et al., 1999; Fiermonte et al., 2003); In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 12807890, 20574716, 31240152, 32340404, 25874378, 23430880, 23247599, 26549653, 18978333, 10369256) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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