chr14-100292357-C-T

Position:

• chr14-100292357-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039355.3(SLC25A29):​c.838G>A​(p.Glu280Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000222 in 1,351,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SLC25A29 NM_001039355.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

SLC25A29 (HGNC:20116): (solute carrier family 25 member 29) This gene encodes a nuclear-encoded mitochondrial protein that is a member of the large family of solute carrier family 25 (SLC25) mitochondrial transporters. The members of this superfamily are involved in numerous metabolic pathways and cell functions. This gene product was previously reported to be a mitochondrial carnitine-acylcarnitine-like (CACL) translocase (PMID:128829710) or an ornithine transporter (designated ORNT3, PMID:19287344), however, a recent study characterized the main role of this protein as a mitochondrial transporter of basic amino acids, with a preference for arginine and lysine (PMID:24652292). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

SLC25A29 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13254574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A29	NM_001039355.3	c.838G>A	p.Glu280Lys	missense_variant	4/4	ENST00000359232.8	NP_001034444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A29	ENST00000359232.8	c.838G>A	p.Glu280Lys	missense_variant	4/4	1	NM_001039355.3	ENSP00000352167.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1351390 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 665450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.838G>A (p.E280K) alteration is located in exon 4 (coding exon 4) of the SLC25A29 gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.082	T;.;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;.;.;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L;.;.;.
PROVEAN	Benign	-0.97	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.0030	B;.;.;.
Vest4		0.27
MutPred		0.47		Gain of methylation at E280 (P = 0.0053);.;.;.;
MVP		0.78
MPC		0.49
ClinPred		0.20	T
GERP RS		4.5
Varity_R		0.056
gMVP		0.76

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: rs1260110874; hg19: chr14-100758694;