chrX-130349297-A-G

Variant names:

• chrX-130349297-A-G
• NM_001282195.2:c.364A>G

Variant summary

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

The NM_001282195.2(SLC25A14):​c.364A>G​(p.Ile122Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,348 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: SLC25A14 NM_001282195.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

SLC25A14 (HGNC:10984): (solute carrier family 25 member 14) Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). Uncoupling proteins separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. Uncoupling proteins facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. This gene is widely expressed in many tissues with the greatest abundance in brain and testis. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been defined on chromosome 4. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282195.2. 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
	SLC25A14	NM_001282195.2	MANE Select	c.364A>G	p.Ile122Val	missense	Exon 5 of 11	NP_001269124.1	O95258-1
	SLC25A14	NM_001282197.2		c.355A>G	p.Ile119Val	missense	Exon 5 of 12	NP_001269126.1	O95258-3
	SLC25A14	NM_001282196.2		c.355A>G	p.Ile119Val	missense	Exon 5 of 11	NP_001269125.1	O95258-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A14	ENST00000545805.6	TSL:5 MANE Select	c.364A>G	p.Ile122Val	missense	Exon 5 of 11	ENSP00000444642.2	O95258-1
	SLC25A14	ENST00000339231.3	TSL:1	c.355A>G	p.Ile119Val	missense	Exon 4 of 11	ENSP00000342797.3	O95258-3
	SLC25A14	ENST00000218197.9	TSL:1	c.364A>G	p.Ile122Val	missense	Exon 4 of 10	ENSP00000218197.5	O95258-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090348 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 356484

African (AFR) AF: 0.00 AC: 0 AN: 26219

American (AMR) AF: 0.00 AC: 0 AN: 35022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19250

East Asian (EAS) AF: 0.00 AC: 0 AN: 30101

South Asian (SAS) AF: 0.00 AC: 0 AN: 53418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836037

Other (OTH) AF: 0.0000218 AC: 1 AN: 45799

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.028	D
Polyphen		0.96	D
Vest4		0.53
MutPred		0.68		Loss of catalytic residue at I122 (P = 0.0818)
MVP		0.88
MPC		1.9
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.55
gMVP		0.85
Mutation Taster		=72/28	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

hg19: chrX-129483271;