13-40793160-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014252.4(SLC25A15):​c.-67A>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,524,934 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0076 ( 43 hom. )

Consequence

SLC25A15
NM_014252.4 splice_region

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.350
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BP6
Variant 13-40793160-A-T is Benign according to our data. Variant chr13-40793160-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 312174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00601 (916/152294) while in subpopulation NFE AF= 0.00923 (628/68026). AF 95% confidence interval is 0.00863. There are 2 homozygotes in gnomad4. There are 431 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC25A15NM_014252.4 linkuse as main transcriptc.-67A>T splice_region_variant 2/7 ENST00000338625.9 NP_055067.1 Q9Y619
SLC25A15NM_014252.4 linkuse as main transcriptc.-67A>T 5_prime_UTR_variant 2/7 ENST00000338625.9 NP_055067.1 Q9Y619

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC25A15ENST00000338625.9 linkuse as main transcriptc.-67A>T splice_region_variant 2/71 NM_014252.4 ENSP00000342267.4 Q9Y619
SLC25A15ENST00000338625 linkuse as main transcriptc.-67A>T 5_prime_UTR_variant 2/71 NM_014252.4 ENSP00000342267.4 Q9Y619

Frequencies

GnomAD3 genomes
AF:
0.00602
AC:
916
AN:
152176
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00167
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00661
Gnomad ASJ
AF:
0.00432
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00810
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00923
Gnomad OTH
AF:
0.00814
GnomAD4 exome
AF:
0.00761
AC:
10441
AN:
1372640
Hom.:
43
Cov.:
20
AF XY:
0.00738
AC XY:
5077
AN XY:
687846
show subpopulations
Gnomad4 AFR exome
AF:
0.00135
Gnomad4 AMR exome
AF:
0.00466
Gnomad4 ASJ exome
AF:
0.00424
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000239
Gnomad4 FIN exome
AF:
0.00907
Gnomad4 NFE exome
AF:
0.00894
Gnomad4 OTH exome
AF:
0.00651
GnomAD4 genome
AF:
0.00601
AC:
916
AN:
152294
Hom.:
2
Cov.:
32
AF XY:
0.00579
AC XY:
431
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00166
Gnomad4 AMR
AF:
0.00660
Gnomad4 ASJ
AF:
0.00432
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00810
Gnomad4 NFE
AF:
0.00923
Gnomad4 OTH
AF:
0.00806
Alfa
AF:
0.00810
Hom.:
0
Bravo
AF:
0.00561
Asia WGS
AF:
0.000866
AC:
4
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2021- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 15, 2021- -
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
2.8
DANN
Benign
0.52

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.

Other links and lift over

dbSNP: rs112276566; hg19: chr13-41367296; API