Genetic Variant SLC25A53:p.Val126Leu (chrX-104104882-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001012755.5(SLC25A53):c.376G>C(p.Val126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,210,106 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 3 hem. )

Consequence

SLC25A53
NM_001012755.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.203

Variant links:

Genes affected

SLC25A53 (HGNC:31894): (solute carrier family 25 member 53) Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC25A53 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.085106194).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A53	NM_001012755.5 link	c.376G>C	p.Val126Leu	missense_variant	Exon 2 of 2	ENST00000594199.3	NP_001012773.2	Q5H9E4
SLC25A53	XM_005262129.6 link	c.376G>C	p.Val126Leu	missense_variant	Exon 2 of 2		XP_005262186.1	Q5H9E4
SLC25A53	XM_011530952.4 link	c.376G>C	p.Val126Leu	missense_variant	Exon 3 of 3		XP_011529254.1	Q5H9E4
SLC25A53	XM_011530953.4 link	c.376G>C	p.Val126Leu	missense_variant	Exon 3 of 3		XP_011529255.1	Q5H9E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A53	ENST00000594199.3 link	c.376G>C	p.Val126Leu	missense_variant	Exon 2 of 2	1	NM_001012755.5	ENSP00000468980.1		Q5H9E4

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111885

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34035

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183061

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67701

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1098221

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363581

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111885

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34035

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>C (p.V126L) alteration is located in exon 2 (coding exon 1) of the SLC25A53 gene. This alteration results from a G to C substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.4

DANN

Benign

0.94

DEOGEN2

Benign

0.062

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.56

M_CAP

Benign

0.011

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.66

PrimateAI

Benign

0.46

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.061

MutPred

0.48

Loss of glycosylation at S124 (P = 0.1675);

MVP

0.51

ClinPred

0.048

GERP RS

2.4

Varity_R

0.062

gMVP

0.55

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