13-40793160-A-T

Variant names:

• chr13-40793160-A-T
• rs112276566
• NM_014252.4:c.-67A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.350
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• ornithine translocase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A15	NM_014252.4	MANE Select	c.-67A>T		splice_region	Exon 2 of 7	NP_055067.1	Q9Y619
	SLC25A15	NM_014252.4	MANE Select	c.-67A>T		5_prime_UTR	Exon 2 of 7	NP_055067.1	Q9Y619

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A15	ENST00000338625.9	TSL:1 MANE Select	c.-67A>T		splice_region	Exon 2 of 7	ENSP00000342267.4	Q9Y619
	SLC25A15	ENST00000338625.9	TSL:1 MANE Select	c.-67A>T		5_prime_UTR	Exon 2 of 7	ENSP00000342267.4	Q9Y619
	SLC25A15	ENST00000707033.1		c.-67A>T		splice_region	Exon 2 of 7	ENSP00000516711.1	Q9Y619

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 916 AN: 152176 Hom.: 2 Cov.: 32

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

African (AFR) AF: 0.00135 AC: 43 AN: 31748

American (AMR) AF: 0.00466 AC: 206 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.00424 AC: 108 AN: 25492

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83800

European-Finnish (FIN) AF: 0.00907 AC: 481 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00894 AC: 9228 AN: 1032162

Other (OTH) AF: 0.00651 AC: 373 AN: 57320

GnomAD4 genome AF: 0.00601 AC: 916 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74460

African (AFR) AF: 0.00166 AC: 69 AN: 41558

American (AMR) AF: 0.00660 AC: 101 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00810 AC: 86 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00923 AC: 628 AN: 68026

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00810 Hom.: 0

Bravo AF: 0.00561

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.8
DANN	Benign	0.52
PhyloP100		-0.35
PromoterAI		0.017	Neutral
Mutation Taster		=294/6	polymorphism

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

Other links and lift over

dbSNP: rs112276566; hg19: chr13-41367296;