chr13-40809579-T-A

Position:

• chr13-40809579-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_014252.4(SLC25A15):​c.818T>A​(p.Met273Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,792 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. M273V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC25A15 NM_014252.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.95

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_014252.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A15	NM_014252.4	c.818T>A	p.Met273Lys	missense_variant	7/7	ENST00000338625.9
TPTE2P5	NR_038259.1	n.452-8855A>T		intron_variant, non_coding_transcript_variant
TPTE2P5	NR_038258.1	n.623-8855A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A15	ENST00000338625.9	c.818T>A	p.Met273Lys	missense_variant	7/7	1	NM_014252.4	P1
SLC25A15	ENST00000707033.1	c.818T>A	p.Met273Lys	missense_variant	7/7			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459792 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726226

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 02, 2021

Variant summary: SLC25A15 c.818T>A (p.Met273Lys) results in a non-conservative amino acid change located in the 3rd mitochondrial substrate/solute carrier repeat (IPR018108) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251132 control chromosomes (gnomAD). The variant has been reported in the literature in a compound heterozygous individual affected with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (Fecarotta_2006). The same authors also reported experimental evidence evaluating an impact on protein function in a later study (Tessa_2009), and demonstrated that the variant protein exhibits low transport activity despite normal insertion in the liposomal membrane. The most pronounced variant effect resulted in 15%-<20% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.052	B
Vest4		0.92
MutPred		0.96		Loss of stability (P = 0.0618);
MVP		0.91
MPC		0.22
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202247808; hg19: chr13-41383715; COSMIC: COSV58558200; COSMIC: COSV58558200;