rs754871147

Positions:

chr3-48858568-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting

The NM_000387.6(SLC25A20):c.779_781del(p.Glu260del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

SLC25A20
NM_000387.6 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.00

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a repeat Solcar 3 (size 86) in uniprot entity MCAT_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000387.6

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000387.6. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A20	NM_000387.6 linkuse as main transcript	c.779_781del	p.Glu260del	inframe_deletion	8/9	ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SLC25A20	ENST00000319017.5 linkuse as main transcript	c.779_781del	p.Glu260del	inframe_deletion	8/9	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5 linkuse as main transcript	c.560_562del	p.Glu187del	inframe_deletion	6/7	3
SLC25A20	ENST00000479050.1 linkuse as main transcript	n.98_100del		non_coding_transcript_exon_variant	1/2	2
SLC25A20	ENST00000440964.1 linkuse as main transcript	c.609_611del		3_prime_UTR_variant, NMD_transcript_variant	9/10	2

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000274

AC:

AN:

251446

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000392

AC:

573

AN:

1461894

Hom.:

AF XY:

0.000407

AC XY:

296

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000434

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000256

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000136

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This variant, c.779_781del, results in the deletion of 1 amino acid(s) of the SLC25A20 protein (p.Glu260del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs754871147, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with carnitine-acylcarnitine translocase deficiency (PMID: 21605995). ClinVar contains an entry for this variant (Variation ID: 345940). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SLC25A20 c.779_781delAAG (p.Glu260del) variant has been identified in a compound heterozygous state with a missense variant in one individual with elevated long chain fatty acids and an acylcarnitine profile consistent with carnitine-acylcarnitine translocase deficiency (Wang et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.001814 in the European (Finnish) population of the Exome Aggregation Consortium. In silico modelling experiments showed that the Glu260 amino acid residue is conserved and critical for maintaining the enzyme cavity and substrate recognition. The evidence for this variant is limited. The p.Glu260del variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for carnitine-acylcarnitine translocase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2021

In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21605995, 32340404) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 29, 2022

Variant summary: SLC25A20 c.779_781delAAG (p.Glu260del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00029 in 282850 control chromosomes, predominantly at a frequency of 0.0018 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC25A20 causing Carnitine-Acylcarnitine Translocase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.779_781delAAG has been reported in the literature in at least one individual affected with Carnitine-Acylcarnitine Translocase Deficiency (Wang_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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