13-40789460-C-G

Variant names:

• chr13-40789460-C-G
• rs541415883
• ENST00000478827.1:n.49C>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000478827.1(SLC25A15):​n.49C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00788 in 151,584 control chromosomes in the GnomAD database, including 7 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 0.0079 (7 hom., cov: 32)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: SLC25A15 ENST00000478827.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -3.99

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-40789460-C-G is Benign according to our data. Variant chr13-40789460-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312169.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00786 (1191/151472) while in subpopulation NFE AF= 0.0147 (996/67712). AF 95% confidence interval is 0.014. There are 7 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A15	ENST00000478827.1	n.49C>G		non_coding_transcript_exon_variant	Exon 1 of 7	5
SLC25A15	ENST00000707033.1	c.-273C>G		upstream_gene_variant				ENSP00000516711.1

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1192 AN: 151364 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00369

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.0268 AC: 3 AN: 112 Hom.: 0 Cov.: 0 AF XY: 0.0119 AC XY: 1 AN XY: 84

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0319

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00786 AC: 1191 AN: 151472 Hom.: 7 Cov.: 32 AF XY: 0.00674 AC XY: 499 AN XY: 74028

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00362

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000680

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.00779

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SLC25A15: BS1, BS2 -

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.6
DANN	Benign	0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs541415883; hg19: chr13-41363596;