X-104104782-T-C

Variant names:

• chrX-104104782-T-C
• rs1556354946
• NM_001012755.5:c.476A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012755.5(SLC25A53):​c.476A>G​(p.Lys159Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,252 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. 13/19 in silico tools predict a benign 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. K159E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC25A53 NM_001012755.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.616
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07358742).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012755.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A53	NM_001012755.5	MANE Select	c.476A>G	p.Lys159Arg	missense	Exon 2 of 2	NP_001012773.2	Q5H9E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A53	ENST00000594199.3	TSL:1 MANE Select	c.476A>G	p.Lys159Arg	missense	Exon 2 of 2	ENSP00000468980.1	Q5H9E4
	SLC25A53	ENST00000905741.1		c.476A>G	p.Lys159Arg	missense	Exon 3 of 3	ENSP00000575800.1
	SLC25A53	ENST00000905742.1		c.476A>G	p.Lys159Arg	missense	Exon 3 of 3	ENSP00000575801.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183184 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098252 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363606

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.0000284 AC: 1 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842139

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.049	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.62
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.50		Loss of ubiquitination at K159 (P = 0.0546)
MVP		0.51
ClinPred		0.27	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.39
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1556354946; hg19: chrX-103349465;