X-104105199-G-T

Position:

• chrX-104105199-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001012755.5(SLC25A53):​c.59C>A​(p.Ala20Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,962 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: SLC25A53 NM_001012755.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034074306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A53	NM_001012755.5	c.59C>A	p.Ala20Asp	missense_variant	2/2	ENST00000594199.3	NP_001012773.2
SLC25A53	XM_005262129.6	c.59C>A	p.Ala20Asp	missense_variant	2/2		XP_005262186.1
SLC25A53	XM_011530952.4	c.59C>A	p.Ala20Asp	missense_variant	3/3		XP_011529254.1
SLC25A53	XM_011530953.4	c.59C>A	p.Ala20Asp	missense_variant	3/3		XP_011529255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A53	ENST00000594199.3	c.59C>A	p.Ala20Asp	missense_variant	2/2	1	NM_001012755.5	ENSP00000468980.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097962 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363318

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Sep 26, 2024

The c.59C>A (p.A20D) alteration is located in exon 2 (coding exon 1) of the SLC25A53 gene. This alteration results from a C to A substitution at nucleotide position 59, causing the alanine (A) at amino acid position 20 to be replaced by an aspartic acid (D). 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	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.28
DANN	Benign	0.92
DEOGEN2	Benign	0.0056	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.31		Gain of ubiquitination at K23 (P = 0.0411);
MVP		0.14
ClinPred		0.037	T
GERP RS		0.72
Varity_R		0.13
gMVP		0.58

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

Other links and lift over

dbSNP: rs2075302741; hg19: chrX-103349882;