Genetic Variant SLC25A53:p.Arg54Gly (chrX-104105098-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001012755.5(SLC25A53):c.160C>G(p.Arg54Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,098,242 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

SLC25A53
NM_001012755.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.39

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A53	NM_001012755.5 link	c.160C>G	p.Arg54Gly	missense_variant	Exon 2 of 2	ENST00000594199.3	NP_001012773.2	Q5H9E4
SLC25A53	XM_005262129.6 link	c.160C>G	p.Arg54Gly	missense_variant	Exon 2 of 2		XP_005262186.1	Q5H9E4
SLC25A53	XM_011530952.4 link	c.160C>G	p.Arg54Gly	missense_variant	Exon 3 of 3		XP_011529254.1	Q5H9E4
SLC25A53	XM_011530953.4 link	c.160C>G	p.Arg54Gly	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.160C>G	p.Arg54Gly	missense_variant	Exon 2 of 2	1	NM_001012755.5	ENSP00000468980.1		Q5H9E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1098242

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

842130

Other (OTH)

AF:

0.0000434

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.160C>G (p.R54G) alteration is located in exon 2 (coding exon 1) of the SLC25A53 gene. This alteration results from a C to G substitution at nucleotide position 160, causing the arginine (R) at amino acid position 54 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.1

PhyloP100

9.4

PrimateAI

Uncertain

0.67

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.73

Loss of MoRF binding (P = 0.0422);

MVP

0.33

ClinPred

0.99

GERP RS

4.0

Varity_R

0.85

gMVP

0.99

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over