Variant chr3-48857718-T-TG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_000387.6(SLC25A20):c.897_898insC(p.Asn300GlnfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC25A20
NM_000387.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.415

Variant links:

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]

SLC25A20 links:

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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;

PM4

Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 314 codons.

PP5

Variant 3-48857718-T-TG is Pathogenic according to our data. Variant chr3-48857718-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 12132.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 linkuse as main transcript	c.897_898insC	p.Asn300GlnfsTer24	frameshift_variant	9/9	ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SLC25A20	ENST00000319017.5 linkuse as main transcript	c.897_898insC	p.Asn300GlnfsTer24	frameshift_variant	9/9	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5 linkuse as main transcript	c.678_679insC	p.Asn227GlnfsTer24	frameshift_variant	7/7	3
SLC25A20	ENST00000479050.1 linkuse as main transcript	n.216_217insC		non_coding_transcript_exon_variant	2/2	2
SLC25A20	ENST00000440964.1 linkuse as main transcript	c.727_728insC		3_prime_UTR_variant, NMD_transcript_variant	10/10	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250746

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135638

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727158

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2021	Variant summary: SLC25A20 c.897dupC (p.Asn300GlnfsX24) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 250746 control chromosomes. c.897dupC has been reported in the literature in at-least two homozygous individuals affected with Carnitine-Acylcarnitine Translocase Deficiency and subsequently cited by others (example, Huizing_1997, Wang_2011, Ijlst_2001, Costa_2003, Palmieri_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in non-detectable to 10% of normal carnitine acylcarnitine translocase (CACT) activity (example, Huizing_1997, IJlst_2001). 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 pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 16, 2023	This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this frameshift affects SLC25A20 function (PMID: 11162577). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 12132). This variant is also known as 955-959insC. This frameshift has been observed in individual(s) with carnitine-acylcarnitine translocase deficiency (PMID: 9399886; Invitae). This sequence change results in a frameshift in the SLC25A20 gene (p.Asn300Glnfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the SLC25A20 protein and extend the protein by 21 additional amino acid residues. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over