chr6-46659031-A-G

Position:

• chr6-46659031-A-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.368A>G​(p.Glu123Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A27 NM_004277.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

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=0.12433013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A27	NM_004277.5	c.368A>G	p.Glu123Gly	missense_variant	3/9	ENST00000371347.10	NP_004268.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A27	ENST00000371347.10	c.368A>G	p.Glu123Gly	missense_variant	3/9	1	NM_004277.5	ENSP00000360398.3
SLC25A27	ENST00000411689.6	c.368A>G	p.Glu123Gly	missense_variant	3/7	1		ENSP00000412024.2
SLC25A27	ENST00000603486.5	c.158A>G	p.Glu53Gly	missense_variant	1/4	5		ENSP00000474781.1
SLC25A27	ENST00000604908.1	n.279A>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Jun 16, 2023

The c.368A>G (p.E123G) alteration is located in exon 3 (coding exon 3) of the SLC25A27 gene. This alteration results from a A to G substitution at nucleotide position 368, causing the glutamic acid (E) at amino acid position 123 to be replaced by a glycine (G). 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	0.074
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.015	.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	2.5	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.48	T;T;.
Sift4G	Benign	0.81	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.098
MutPred		0.43		Loss of solvent accessibility (P = 0.0387);Loss of solvent accessibility (P = 0.0387);.;
MVP		0.69
MPC		0.54
ClinPred		0.61	D
GERP RS		4.2
Varity_R		0.086
gMVP		0.68

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: chr6-46626768;