chr3-48884134-A-C

Position:

chr3-48884134-A-C

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

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.68

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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	Protein	UniProt
SLC25A20	NM_000387.6 linkuse as main transcript	c.199-10T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000319017.5	NP_000378.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
SLC25A20	ENST00000319017.5 linkuse as main transcript	c.199-10T>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000387.6	ENSP00000326305	P1
SLC25A20	ENST00000430379.5 linkuse as main transcript	c.198+7846T>G	intron_variant	3		ENSP00000388986
SLC25A20	ENST00000440964.1 linkuse as main transcript	c.*29-10T>G	splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	2		ENSP00000388563

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000722

AC:

AN:

249284

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460582

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000808

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.0000340

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

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	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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‚Äìacylcarnitine 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. -
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, no assertion criteria provided	literature only	OMIM	Dec 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	May 10, 2019	- -
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). -

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) -

SLC25A20-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

The SLC25A20 c.199-10T>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous and homozygous state in multiple patients with autosomal recessive carnitine-acylcarnitine translocase deficiency (Ogawa et al. 2000. PubMed ID: 10697964, Tang et al. 2019. PubMed ID: 31108048, Vatanavicharn et al. 2015. PubMed ID: 25459972). RNA studies showed that this variant leads to aberrant splicing and truncation of the protein (Ogawa et al. 2000. PubMed ID: 10697964). This variant is reported in 0.095% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: -1

DS_AL_spliceai

0.65

Position offset: -10

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