NM_001379210.1:c.443T>G

Variant names:

• chr3-66263369-T-G
• rs869025313
• NM_001379210.1:c.443T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001379210.1(SLC25A26):​c.443T>G​(p.Val148Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,457,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SLC25A26 NM_001379210.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.64
• Publications: 4 publications found

Genes affected

SLC25A26 (HGNC:20661): (solute carrier family 25 member 26) This gene is a member of the mitochondrial carrier family which includes nuclear-encoded transporters localized on the inner mitochondrial membranes. Members of the family transport important small molecules across the mitochondrial inner membrane. This protein is involved in the transport of S-adenosylmethionine (SAM) into the mitochondria. Mutations in this gene are associated with combined oxidative phosphorylation deficiency 28. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2017]

SLC25A26 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 28

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 3-66263369-T-G is Pathogenic according to our data. Variant chr3-66263369-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 222006.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379210.1. 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
	SLC25A26	NM_001379210.1	MANE Select	c.443T>G	p.Val148Gly	missense	Exon 5 of 10	NP_001366139.1	Q70HW3-1
	SLC25A26	NM_001400705.1		c.443T>G	p.Val148Gly	missense	Exon 5 of 11	NP_001387634.1
	SLC25A26	NM_173471.4		c.443T>G	p.Val148Gly	missense	Exon 6 of 11	NP_775742.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A26	ENST00000354883.11	TSL:2 MANE Select	c.443T>G	p.Val148Gly	missense	Exon 5 of 10	ENSP00000346955.6	Q70HW3-1
	SLC25A26	ENST00000336733.10	TSL:1	c.179T>G	p.Val60Gly	missense	Exon 4 of 9	ENSP00000336801.5	Q70HW3-2
	SLC25A26	ENST00000464350.6	TSL:1	n.179T>G		non_coding_transcript_exon	Exon 4 of 13	ENSP00000432574.2	H0YCZ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1457676 Hom.: 0 Cov.: 28 AF XY: 0.00000827 AC XY: 6 AN XY: 725090

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108996

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation deficiency 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.65
MutPred		0.82		Loss of stability (P = 0.0148)
MVP		0.52
MPC		0.20
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.86

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: rs869025313; hg19: chr3-66313793;