rs886041081

Variant names:

• chr4-185144891-G-A
• rs886041081
• NM_001151.4:c.239G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001151.4(SLC25A4):​c.239G>A​(p.Arg80His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A4 NM_001151.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0
• Publications: 22 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a repeat Solcar 1 (size 92) in uniprot entity ADT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001151.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-185144890-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 635018.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 4-185144891-G-A is Pathogenic according to our data. Variant chr4-185144891-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 253037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.239G>A	p.Arg80His	missense_variant	Exon 2 of 4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.239G>A	p.Arg80His	missense_variant	Exon 2 of 4	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.239G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000435 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant Pathogenic:2

Jul 31, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Oct 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 80 of the SLC25A4 protein (p.Arg80His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SLC25A4-related conditions (PMID: 27693233, 32827528). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 253037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC25A4 protein function. Experimental studies have shown that this missense change affects SLC25A4 function (PMID: 27693233). For these reasons, this variant has been classified as Pathogenic. -

Dec 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect, as structural analysis suggests R80H affects the proposed substrate-binding site, and in-vitro assays detected a reduced ADP transport rate in the R80H mutant construct as compared to wild type (Thompson et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27693233, 30009132, 31271879, 32827528) -

Inborn genetic diseases Pathogenic:1

Sep 29, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:1

Aug 06, 2016

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.95
MutPred		0.78		Loss of methylation at R80 (P = 0.0408);
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.95
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886041081; hg19: chr4-186066045; COSMIC: COSV55669674;