13-40799183-G-C

Variant names:

• chr13-40799183-G-C
• rs34615430
• NM_014252.4:c.182G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_014252.4(SLC25A15):​c.182G>C​(p.Arg61Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R61H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC25A15 NM_014252.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52
• Publications: 7 publications found

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]

SUGT1P3 (HGNC:):

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A15	NM_014252.4	MANE Select	c.182G>C	p.Arg61Pro	missense	Exon 3 of 7	NP_055067.1
	TPTE2P5	NR_038258.1		n.2164C>G		non_coding_transcript_exon	Exon 8 of 8
	TPTE2P5	NR_038259.1		n.1993C>G		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A15	ENST00000338625.9	TSL:1 MANE Select	c.182G>C	p.Arg61Pro	missense	Exon 3 of 7	ENSP00000342267.4
	SLC25A15	ENST00000707033.1		c.182G>C	p.Arg61Pro	missense	Exon 3 of 7	ENSP00000516711.1
	SLC25A15	ENST00000417731.5	TSL:5	c.182G>C	p.Arg61Pro	missense	Exon 2 of 3	ENSP00000415826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 8

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Uncertain:1

Sep 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with proline at codon 61 of the SLC25A15 protein (p.Arg61Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC25A15-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.035	D
Polyphen		0.073	B
Vest4		0.81
MutPred		0.70		Loss of methylation at R61 (P = 0.0033)
MVP		0.86
MPC		0.16
ClinPred		0.89	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.96
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs34615430; hg19: chr13-41373319;