Genetic Variant SLC25A27:p.His174Tyr (chr6-46664787-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004277.5(SLC25A27):c.520C>T(p.His174Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000238 in 1,599,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

SLC25A27
NM_004277.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A27	NM_004277.5 link	c.520C>T	p.His174Tyr	missense_variant	Exon 5 of 9	ENST00000371347.10	NP_004268.3	O95847-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A27	ENST00000371347.10 link	c.520C>T	p.His174Tyr	missense_variant	Exon 5 of 9	1	NM_004277.5	ENSP00000360398.3		O95847-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000698

AC:

AN:

243608

Hom.:

AF XY:

0.0000453

AC XY:

AN XY:

132344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000916

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000235

AC:

AN:

1447214

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

720554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000764

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000563

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.520C>T (p.H174Y) alteration is located in exon 5 (coding exon 5) of the SLC25A27 gene. This alteration results from a C to T substitution at nucleotide position 520, causing the histidine (H) at amino acid position 174 to be replaced by a tyrosine (Y). 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

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.029

.;T;.

Eigen

Benign

0.063

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0083

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.58

N;N;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

1.6

N;N;.

REVEL

Benign

0.20

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.30

MVP

0.65

MPC

0.54

ClinPred

0.093

GERP RS

5.1

Varity_R

0.11

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over