Variant 13-40793237-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_014252.4(SLC25A15):c.11A>G(p.Asn4Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SLC25A15
NM_014252.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

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:

SLC25A15 (HGNC:):

SLC25A15 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.11130804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A15	NM_014252.4 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	2/7	ENST00000338625.9	NP_055067.1	Q9Y619

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A15	ENST00000338625.9 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	2/7	1	NM_014252.4	ENSP00000342267.4		Q9Y619

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251284

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135812

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 4 of the SLC25A15 protein (p.Asn4Ser). This variant is present in population databases (rs778928196, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SLC25A15-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.54

T;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.22

N;.

MutationTaster

Benign

0.76

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.21

Sift

Benign

0.48

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

B;.

Vest4

0.15

MutPred

0.25

Gain of glycosylation at N4 (P = 0.0191);Gain of glycosylation at N4 (P = 0.0191);

MVP

0.68

MPC

0.083

ClinPred

0.054

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.73

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