rs35989076

chr3-48858577-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000387.6(SLC25A20):c.773G>A(p.Arg258Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,614,194 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: SLC25A20 NM_000387.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.80

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 -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034131408).
• BP6: Variant 3-48858577-C-T is Benign according to our data. Variant chr3-48858577-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00315 (480/152302) while in subpopulation AFR AF= 0.0109 (455/41556). AF 95% confidence interval is 0.0101. There are 5 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A20	NM_000387.6	c.773G>A	p.Arg258Gln	missense_variant	8/9	ENST00000319017.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A20	ENST00000319017.5	c.773G>A	p.Arg258Gln	missense_variant	8/9	1	NM_000387.6	P1
SLC25A20	ENST00000430379.5	c.554G>A	p.Arg185Gln	missense_variant	6/7	3
SLC25A20	ENST00000479050.1	n.92G>A		non_coding_transcript_exon_variant	1/2	2
SLC25A20	ENST00000440964.1	c.*603G>A		3_prime_UTR_variant, NMD_transcript_variant	9/10	2

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152184 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000927 AC: 233 AN: 251434 Hom.: 5 AF XY: 0.000677 AC XY: 92 AN XY: 135880

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000838

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: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000324 AC: 474 AN: 1461892 Hom.: 2 Cov.: 31 AF XY: 0.000276 AC XY: 201 AN XY: 727246

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152302 Hom.: 5 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74482

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000530 Hom.: 2

Bravo AF: 0.00353

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine acylcarnitine translocase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 21, 2015

- -

SLC25A20-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.27
Sift	Benign	0.23	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.057	B;B
Vest4		0.21
MVP		0.86
MPC		0.31
ClinPred		0.024	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.83

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

Other links and lift over

dbSNP: rs35989076; hg19: chr3-48896010;