4-185143377-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_001151.4(SLC25A4):c.5G>T(p.Gly2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. G2D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SLC25A4
NM_001151.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

Publications

2 publications found

Variant links:

Genes affected

SLC25A4 (HGNC:10990): (solute carrier family 25 member 4) This gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm. The protein forms a homodimer embedded in the inner mitochondria membrane. Mutations in this gene have been shown to result in autosomal dominant progressive external opthalmoplegia and familial hypertrophic cardiomyopathy. [provided by RefSeq, Jun 2013]

SLC25A4 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
Fontaine progeroid syndrome
Inheritance: AD Classification: STRONG Submitted by: G2P
mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant progressive external ophthalmoplegia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sengers syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SLC25A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a chain ADP/ATP translocase 1 (size 296) in uniprot entity ADT1_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in NM_001151.4

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 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.8742 (below the threshold of 3.09). Trascript score misZ: 2.2652 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial disease, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, Fontaine progeroid syndrome, Leigh syndrome, Sengers syndrome, autosomal dominant progressive external ophthalmoplegia.

BP4

Computational evidence support a benign effect (MetaRNN=0.39629608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4 link	c.5G>T	p.Gly2Val	missense_variant	Exon 1 of 4	ENST00000281456.11	NP_001142.2	P12235A0A0S2Z3H3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11 link	c.5G>T	p.Gly2Val	missense_variant	Exon 1 of 4	1	NM_001151.4	ENSP00000281456.5		P12235
SLC25A4	ENST00000491736.1 link	n.5G>T		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000476711.1		V9GYG0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000137

AC:

AN:

145714

AF XY:

0.0000259

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1375060

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

678846

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29948

American (AMR)

AF:

0.00

AC:

AN:

34214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24440

East Asian (EAS)

AF:

0.0000292

AC:

AN:

34202

South Asian (SAS)

AF:

0.00

AC:

AN:

77526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

9.40e-7

AC:

AN:

1064194

Other (OTH)

AF:

0.00

AC:

AN:

56720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Benign

-0.13

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.21

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.7

PhyloP100

3.4

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Benign

0.099

Sift4G

Benign

0.12

Polyphen

0.0050

Vest4

0.17

MutPred

0.38

Loss of disorder (P = 0.0455);

MVP

0.85

MPC

1.1

ClinPred

0.20

GERP RS

3.4

PromoterAI

0.069

Neutral

(source)

Varity_R

0.25

gMVP

0.43

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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4-185143377-G-T

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