Genetic Variant SLC25A45:p.His149Arg (chr11-65376970-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182556.4(SLC25A45):c.446A>G(p.His149Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000924 in 1,613,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

SLC25A45
NM_182556.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.55

Variant links:

Genes affected

SLC25A45 (HGNC:27442): (solute carrier family 25 member 45) Predicted to enable acyl carnitine transmembrane transporter activity. Predicted to be involved in acyl carnitine transport and amino acid transport. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC25A45 links:

FRMD8 (HGNC:25462): (FERM domain containing 8) Involved in positive regulation of tumor necrosis factor production. Located in several cellular components, including centriolar satellite; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

FRMD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.19598383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A45	NM_182556.4 link	c.446A>G	p.His149Arg	missense_variant	Exon 6 of 7	ENST00000398802.6	NP_872362.4	Q8N413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A45	ENST00000398802.6 link	c.446A>G	p.His149Arg	missense_variant	Exon 6 of 7	5	NM_182556.4	ENSP00000381782.1		Q8N413-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000198

AC:

AN:

247280

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

134292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00454

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000924

AC:

135

AN:

1460970

Hom.:

Cov.:

AF XY:

0.0000936

AC XY:

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000141

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446A>G (p.H149R) alteration is located in exon 6 (coding exon 5) of the SLC25A45 gene. This alteration results from a A to G substitution at nucleotide position 446, causing the histidine (H) at amino acid position 149 to be replaced by an arginine (R). 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

0.30

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.7

L;.;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-6.5

D;D;D;D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.66

MVP

0.61

MPC

0.70

ClinPred

0.33

GERP RS

5.1

Varity_R

0.86

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

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