rs104893873

Variant names:

• chr4-185144992-G-A
• rs104893873
• NM_001151.4:c.340G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-185144992-G-A
• chr4-185144992-G-C
• chr4-185144992-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001151.4(SLC25A4):​c.340G>A​(p.Ala114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A4 NM_001151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 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: Likely_pathogenic. The variant received 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-185144992-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18245.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001151.4. 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
	SLC25A4	NM_001151.4	MANE Select	c.340G>A	p.Ala114Thr	missense	Exon 2 of 4	NP_001142.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A4	ENST00000281456.11	TSL:1 MANE Select	c.340G>A	p.Ala114Thr	missense	Exon 2 of 4	ENSP00000281456.5
	SLC25A4	ENST00000491736.1	TSL:5	n.340G>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000476711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.7	L
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.088	T
Polyphen		0.0070	B
Vest4		0.73
MutPred		0.49		Loss of catalytic residue at A114 (P = 0.0173)
MVP		0.83
MPC		0.95
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.85
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs104893873; hg19: chr4-186066146;