9-128105775-C-G

Variant names:

• chr9-128105775-C-G
• rs369203375
• NM_001330988.2:c.830C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001330988.2(SLC25A25):​c.830C>G​(p.Thr277Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T277I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SLC25A25 NM_001330988.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 1 publications found

Genes affected

SLC25A25 (HGNC:20663): (solute carrier family 25 member 25) The protein encoded by this gene belongs to the family of calcium-binding mitochondrial carriers, with a characteristic mitochondrial carrier domain at the C-terminus. These proteins are found in the inner membranes of mitochondria, and function as transport proteins. They shuttle metabolites, nucleotides and cofactors through the mitochondrial membrane and thereby connect and/or regulate cytoplasm and matrix functions. This protein may function as an ATP-Mg/Pi carrier that mediates the transport of Mg-ATP in exchange for phosphate, and likely responsible for the net uptake or efflux of adenine nucleotides into or from the mitochondria. Alternatively spliced transcript variants encoding different isoforms with a common C-terminus but variable N-termini have been described for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.653 (below the threshold of 3.09). Trascript score misZ: 1.6856 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.18799955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330988.2. 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
	SLC25A25	NM_001330988.2	MANE Select	c.830C>G	p.Thr277Ser	missense	Exon 7 of 11	NP_001317917.1	Q6KCM7-3
	SLC25A25	NM_001006641.4		c.794C>G	p.Thr265Ser	missense	Exon 6 of 10	NP_001006642.1	Q6KCM7-2
	SLC25A25	NM_001265614.3		c.788C>G	p.Thr263Ser	missense	Exon 7 of 11	NP_001252543.1	Q6KCM7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A25	ENST00000373069.10	TSL:5 MANE Select	c.830C>G	p.Thr277Ser	missense	Exon 7 of 11	ENSP00000362160.5	Q6KCM7-3
	SLC25A25	ENST00000373068.6	TSL:1	c.794C>G	p.Thr265Ser	missense	Exon 6 of 10	ENSP00000362159.2	Q6KCM7-2
	SLC25A25	ENST00000373066.9	TSL:1	c.788C>G	p.Thr263Ser	missense	Exon 7 of 11	ENSP00000362157.5	Q6KCM7-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.0070	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.080	N
PhyloP100		3.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.30
Sift	Benign	0.21	T
Sift4G	Benign	0.16	T
Polyphen		0.12	B
Vest4		0.37
MutPred		0.40		Gain of disorder (P = 0.067)
MVP		0.043
MPC		0.52
ClinPred		0.57	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42
Mutation Taster		=75/25	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: rs369203375; hg19: chr9-130868054;