3-66262051-G-C

Variant names:

• chr3-66262051-G-C
• rs774532404
• NM_001379210.1:c.301G>C

Variant summary

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

The NM_001379210.1(SLC25A26):​c.301G>C​(p.Val101Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000711 in 1,405,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V101I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC25A26 NM_001379210.1 missense, splice_region
• Scores: Splicing: ADA: 0.2680
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.60
• Publications: 2 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: 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_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.301G>C	p.Val101Leu	missense splice_region	Exon 4 of 10	NP_001366139.1	Q70HW3-1
	SLC25A26	NM_001400705.1		c.301G>C	p.Val101Leu	missense splice_region	Exon 4 of 11	NP_001387634.1
	SLC25A26	NM_173471.4		c.301G>C	p.Val101Leu	missense splice_region	Exon 5 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.301G>C	p.Val101Leu	missense splice_region	Exon 4 of 10	ENSP00000346955.6	Q70HW3-1
	SLC25A26	ENST00000336733.10	TSL:1	c.37G>C	p.Val13Leu	missense splice_region	Exon 3 of 9	ENSP00000336801.5	Q70HW3-2
	SLC25A26	ENST00000464350.6	TSL:1	n.37G>C		splice_region non_coding_transcript_exon	Exon 3 of 13	ENSP00000432574.2	H0YCZ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1405808 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 696308

African (AFR) AF: 0.00 AC: 0 AN: 31846

American (AMR) AF: 0.00 AC: 0 AN: 36846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 38556

South Asian (SAS) AF: 0.00 AC: 0 AN: 77320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080344

Other (OTH) AF: 0.0000171 AC: 1 AN: 58504

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.29
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.0060	B
Vest4		0.54
MutPred		0.51		Gain of stability (P = 0.1848)
MVP		0.34
MPC		0.025
ClinPred		0.73	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.86
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.050		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: rs774532404; hg19: chr3-66312475;