3-48857351-G-A

Variant names:

• chr3-48857351-G-A
• rs116681393
• NM_000387.6:c.*359C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 0 publications found

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]

PRKAR2A-AS1 (HGNC:40471): (PRKAR2A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A20	NM_000387.6	c.*359C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000319017.5	NP_000378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A20	ENST00000319017.5	c.*359C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000387.6	ENSP00000326305.4

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

African (AFR) AF: 0.000434 AC: 2 AN: 4604

American (AMR) AF: 0.00240 AC: 16 AN: 6656

Ashkenazi Jewish (ASJ) AF: 0.00669 AC: 25 AN: 3736

East Asian (EAS) AF: 0.00 AC: 0 AN: 7006

South Asian (SAS) AF: 0.00464 AC: 122 AN: 26274

European-Finnish (FIN) AF: 0.00254 AC: 18 AN: 7076

Middle Eastern (MID) AF: 0.0262 AC: 14 AN: 534

European-Non Finnish (NFE) AF: 0.00529 AC: 457 AN: 86320

Other (OTH) AF: 0.00459 AC: 35 AN: 7628

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

African (AFR) AF: 0.000601 AC: 25 AN: 41568

American (AMR) AF: 0.00432 AC: 66 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00520 AC: 25 AN: 4812

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116681393; hg19: chr3-48894784;