rs869025314

Variant names:

• chr3-66262055-C-A
• rs869025314
• NM_001379210.1:c.305C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-66262055-C-A
• chr3-66262055-C-G
• chr3-66262055-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001400705.1(SLC25A26):​c.305C>A​(p.Ala102Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,412,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A102V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC25A26 NM_001400705.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-66262055-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222007.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001400705.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A26	NM_001379210.1	MANE Select	c.305C>A	p.Ala102Asp	missense	Exon 4 of 10	NP_001366139.1
	SLC25A26	NM_001400705.1		c.305C>A	p.Ala102Asp	missense	Exon 4 of 11	NP_001387634.1
	SLC25A26	NM_173471.4		c.305C>A	p.Ala102Asp	missense	Exon 5 of 11	NP_775742.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A26	ENST00000354883.11	TSL:2 MANE Select	c.305C>A	p.Ala102Asp	missense	Exon 4 of 10	ENSP00000346955.6
	SLC25A26	ENST00000336733.10	TSL:1	c.41C>A	p.Ala14Asp	missense	Exon 3 of 9	ENSP00000336801.5
	SLC25A26	ENST00000464350.6	TSL:1	n.41C>A		non_coding_transcript_exon	Exon 3 of 13	ENSP00000432574.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412392 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 699698

African (AFR) AF: 0.00 AC: 0 AN: 32050

American (AMR) AF: 0.00 AC: 0 AN: 37718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 38706

South Asian (SAS) AF: 0.00 AC: 0 AN: 78034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084506

Other (OTH) AF: 0.0000170 AC: 1 AN: 58730

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.82		Loss of methylation at R106 (P = 0.154)
MVP		0.50
MPC		0.22
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=23/77	disease causing

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: rs869025314; hg19: chr3-66312479;