3-48857351-G-A

Position:

• chr3-48857351-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000387.6(SLC25A20):​c.*359C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 302,120 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (4 hom.)
• Consequence: SLC25A20 NM_000387.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00386 (588/152286) while in subpopulation NFE AF= 0.00556 (378/68022). AF 95% confidence interval is 0.0051. There are 2 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A20	NM_000387.6	c.*359C>T		3_prime_UTR_variant	9/9	ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A20	ENST00000319017.5	c.*359C>T		3_prime_UTR_variant	9/9	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5	c.*359C>T		3_prime_UTR_variant	7/7	3
SLC25A20	ENST00000479050.1	n.584C>T		non_coding_transcript_exon_variant	2/2	2
SLC25A20	ENST00000440964.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00460 AC: 689 AN: 149834 Hom.: 4 Cov.: 0 AF XY: 0.00463 AC XY: 373 AN XY: 80508

Gnomad4 AFR exome AF: 0.000434

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.00669

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00464

Gnomad4 FIN exome AF: 0.00254

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00386 AC: 588 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74464

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00520

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00556

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00414

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs116681393; hg19: chr3-48894784;