rs541208710
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000387.6(SLC25A20):c.199-10T>G variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0000254 in 1,612,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
SLC25A20
NM_000387.6 splice_polypyrimidine_tract, intron
NM_000387.6 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.68
Genes affected
SLC25A20 (HGNC:1421): (solute carrier family 25 member 20) This gene product is one of several closely related mitochondrial-membrane carrier proteins that shuttle substrates between cytosol and the intramitochondrial matrix space. This protein mediates the transport of acylcarnitines into mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. Mutations in this gene are associated with carnitine-acylcarnitine translocase deficiency, which can cause a variety of pathological conditions such as hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and is usually lethal in new born and infants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-48884134-A-C is Pathogenic according to our data. Variant chr3-48884134-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC25A20 | NM_000387.6 | c.199-10T>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000319017.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC25A20 | ENST00000319017.5 | c.199-10T>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000387.6 | P1 | |||
SLC25A20 | ENST00000430379.5 | c.198+7846T>G | intron_variant | 3 | |||||
SLC25A20 | ENST00000440964.1 | c.*29-10T>G | splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000722 AC: 18AN: 249284Hom.: 0 AF XY: 0.0000741 AC XY: 10AN XY: 134920
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460582Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 726604
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carnitine acylcarnitine translocase deficiency Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2017 | Variant summary: The SLC25A20 c.199-10T>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict the creation or enhancement of a cryptic splice donor site along with the weakening of a canonical splicing acceptor site. Functional studies have shown the patients with this variant in compound heterozygosity had exon 3/4 skipping, and abberant splicing was also observed in patients and parents who had coding variants suggesting coding sequence mutations might contribute to the presence of aberrantly spliced mRNA (Hsu_2001). The variant was found in numerous affected individuals both in the homozygous and heterozygous state, and the variant has been suggested as an Asian founder mutation. This variant was found in 4/121236 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC25A20 variant (0.001118). In addition, one reputable clinical diagnostic laboratory/multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Molecular Medicine, Children’s Hospital of Fudan University | May 10, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 26, 2020 | The SLC25A20:c.199-10T>G variant is a single nucleotide substitution which results in aberrant splicing. The variant has been reported in the literature as homozygous or heterozygous in combination with another SLC25A20 variant in affected patients (PMID: 25459972, PMID: 25459972) . It has been described as a founder mutation in East Asian populations. RNA studies demonstrate exon 3 and exon 3/4 skipping which is predicted to be detrimental to protein function (PMID: 10697964). It is present in population databases at 0.007% (20 het/280674 allele count) (PP). Splice prediction programs in Alamut indicate that the variant may disrupt the exon 3 acceptor site. The variant is described in ClinVar as pathogenic and HGMD (2019.4) as disease causing (PP5). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change falls in intron 2 of the SLC25A20 gene. It does not directly change the encoded amino acid sequence of the SLC25A20 protein. This variant is present in population databases (rs541208710, gnomAD 0.09%). This variant has been observed in individuals with carnitine–acylcarnitine translocase deficiency (PMID: 10697964, 24088670, 25459972, 26238931, 27066551). It has also been observed to segregate with disease in related individuals. This variant is also known as 261-10T>G. ClinVar contains an entry for this variant (Variation ID: 12137). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2021 | Reverse transcriptase PCR in patient fibroblasts indicate c.199-10 T>G results in abnormal gene splicing (Ogawa et al., 2000); This variant is associated with the following publications: (PMID: 25459972, 29137068, 10697964, 15363639, 11592821, 29996190, 31108048, 31965297, 31501239, 32411386, 33634872, 33194920, 32778825, 24088670) - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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DS_AL_spliceai
Position offset: -10
Find out detailed SpliceAI scores and Pangolin per-transcript scores at