chr13-40799111-T-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_014252.4(SLC25A15):​c.110T>C​(p.Met37Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M37R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC25A15
NM_014252.4 missense

Scores

9
9
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.10

Publications

4 publications found
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]
TPTE2P5 (HGNC:42356): (TPTE2 pseudogene 5)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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, 4 uncertain in NM_014252.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr13-40799111-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 5997.Status of the report is no_assertion_criteria_provided, 0 stars.
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, 0.961

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC25A15NM_014252.4 linkc.110T>C p.Met37Thr missense_variant Exon 3 of 7 ENST00000338625.9 NP_055067.1 Q9Y619
TPTE2P5NR_038258.1 linkn.2236A>G non_coding_transcript_exon_variant Exon 8 of 8
TPTE2P5NR_038259.1 linkn.2065A>G non_coding_transcript_exon_variant Exon 6 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC25A15ENST00000338625.9 linkc.110T>C p.Met37Thr missense_variant Exon 3 of 7 1 NM_014252.4 ENSP00000342267.4 Q9Y619

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251496
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461888
Hom.:
0
Cov.:
35
AF XY:
0.00000688
AC XY:
5
AN XY:
727246
show subpopulations
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:
0.00000989
AC:
11
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000197
Hom.:
0
Bravo
AF:
0.0000113
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Pathogenic
3.7
H;.
PhyloP100
6.1
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.91
MutPred
0.84
Gain of methylation at K36 (P = 0.0343);Gain of methylation at K36 (P = 0.0343);
MVP
0.96
MPC
0.54
ClinPred
0.98
D
GERP RS
4.5
Varity_R
0.94
gMVP
0.96
Mutation Taster
=16/84
disease causing

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

Other links and lift over

dbSNP: rs121908533; hg19: chr13-41373247; API