6-46655986-T-G

Position:

• chr6-46655986-T-G

Variant summary

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

The NM_004277.5(SLC25A27):​c.250T>G​(p.Phe84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,460,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: SLC25A27 NM_004277.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

SLC25A27 (HGNC:21065): (solute carrier family 25 member 27) Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. Transcripts of this gene are only detected in brain tissue and are specifically modulated by various environmental conditions. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]

SLC25A27 (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=0.16572514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A27	NM_004277.5	c.250T>G	p.Phe84Val	missense_variant	2/9	ENST00000371347.10	NP_004268.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A27	ENST00000371347.10	c.250T>G	p.Phe84Val	missense_variant	2/9	1	NM_004277.5	ENSP00000360398.3
SLC25A27	ENST00000411689.6	c.250T>G	p.Phe84Val	missense_variant	2/7	1		ENSP00000412024.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460198 Hom.: 1 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726356

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: 0.0000306

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 12, 2024

The c.250T>G (p.F84V) alteration is located in exon 2 (coding exon 2) of the SLC25A27 gene. This alteration results from a T to G substitution at nucleotide position 250, causing the phenylalanine (F) at amino acid position 84 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.0021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.99	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.19
Sift	Benign	0.43	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0040	.;B
Vest4		0.24
MutPred		0.48		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.41
MPC		0.61
ClinPred		0.31	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46623723;