Genetic Variant SLC25A26:p.Val101Leu (chr3-66262051-G-C) – ACMG Classification: Uncertain_significance (2 pts)

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

Variant links:

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

SLC25A26 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A26	NM_001379210.1 link	c.301G>C	p.Val101Leu	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000354883.11	NP_001366139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A26	ENST00000354883.11 link	c.301G>C	p.Val101Leu	missense_variant, splice_region_variant	Exon 4 of 10	2	NM_001379210.1	ENSP00000346955.6		Q70HW3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1405808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31846

American (AMR)

AF:

0.00

AC:

AN:

36846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25146

East Asian (EAS)

AF:

0.00

AC:

AN:

38556

South Asian (SAS)

AF:

0.00

AC:

AN:

77320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080344

Other (OTH)

AF:

0.0000171

AC:

AN:

58504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

L;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

N;N;.

REVEL

Benign

0.29

Sift

Benign

0.19

T;T;.

Sift4G

Benign

0.24

T;T;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

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

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over