rs757552268

Positions:

chr3-48883995-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_StrongPM2PP3_ModeratePP5_Very_Strong

The NM_000387.6(SLC25A20):c.326+1del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

SLC25A20
NM_000387.6 splice_donor

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1401766 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of 0 (no position change), new splice context is: tcaGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-48883995-AC-A is Pathogenic according to our data. Variant chr3-48883995-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 345943.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.326+1del		splice_donor_variant		ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
SLC25A20	ENST00000319017.5 linkuse as main transcript	c.326+1del	splice_donor_variant	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5 linkuse as main transcript	c.198+7984del	intron_variant	3
SLC25A20	ENST00000440964.1 linkuse as main transcript	c.*156+1del	splice_donor_variant, NMD_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249670

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135098

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:

0.0000803

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1461092

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000675

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2018	Variant summary: SLC25A20 c.326+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Five out five computational tools predict a significant impact on normal splicing consistent with multiple publications reporting experimental evidence that this variant affects mRNA splicing (Yang_2001, Hsu_2001). The variant allele was found at a frequency of 2.5e-05 in 244468 control chromosomes (gnomAD). c.326+1delG has been reported in the literature in multiple individuals affected with Carnitine-Acylcarnitine Translocase Deficiency (Yang_2001, Hsu_2001, Korman_2006), at-least one of whom was reported to have no Carnitine Acyltranslocase activity (Korman_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SLC25A20 c.326+1delG variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of four individuals with carnitine-acylcarnitine translocase deficiency including in a homozygous state in two siblings and in a compound heterozygous state in two unrelated individuals (Yang et al. 2001; Hsu et al. 2001; Korman et al. 2006). The c.326+1delG variant was absent from 30 healthy controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed a total absence of CACT enzyme activity while RT-PCR analysis revealed the variant resulted in skipping of either exon 3 or both exon 3 and exon 4 in individual RNA (Yang et al. 2001; Hsu et al. 2001; Korman et al. 2006). Based on the collective evidence and potential impact of splice site variants, the c.326+1delG variant is classified as pathogenic for carnitine-acylcarnitine translocase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (Splice site) in the SLC25A20 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A20 are known to be pathogenic (PMID: 25614308). This variant is present in population databases (rs757552268, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with carnitine-acylcarnitine translocase deficiency (PMID: 11350184, 11592821, 15365988, 16919490). This variant is also known as 388 1-G deletion and 326+1del. ClinVar contains an entry for this variant (Variation ID: 345943). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2023

Observed in trans with another variant in SLC25A20 in unrelated patients with SLC25A20-related carnitine-acylcarnitine translocase deficiency (Hsu et al., 2001; Korman et al., 2006); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32070364, 25614308, 33634872, 31589614, 36109795, 11592821, 11350184, 16919490) -

SLC25A20-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

The SLC25A20 c.326+1delG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in the homozygous or compound heterozygous state in clinically affected individuals with enzymatically or biochemically confirmed carnitine-acylcarnitine translocase (CACT) deficiency (Yang et al 2001. PubMed ID: 11350184, described as 388g deletion; Korman SH et al 2006. PubMed ID: 16919490; Bhattacharya K et al 2020. PubMed ID: 32070364). RNA studies have shown that the c.326+1del variant leads to aberrant splicing, primarily skipping of SLC25A20 exon 3 or exons 3 and 4 together (Yang et al 2001. PubMed ID: 11350184; Korman SH et al 2006. PubMed ID: 16919490). This variant is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48921428-AC-A). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.88

Position offset: 3

DS_DL_spliceai

0.99

Position offset: 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