NM_001151.4:c.73G>A

Variant names:

• chr4-185143445-G-A
• rs560967545
• NM_001151.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1 PP2 BP4_Moderate BS1_Supporting

The NM_001151.4(SLC25A4):​c.73G>A​(p.Ala25Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000596 in 1,510,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SLC25A4 NM_001151.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.38
• 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: Uncertain_significance. The variant received 0 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
• 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=0.20782462).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000198 (3/151772) while in subpopulation EAS AF = 0.000583 (3/5150). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.73G>A	p.Ala25Thr	missense_variant	Exon 1 of 4	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.73G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151664 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000156 AC: 2 AN: 128374 AF XY: 0.0000146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000441 AC: 6 AN: 1359014 Hom.: 0 Cov.: 29 AF XY: 0.00000597 AC XY: 4 AN XY: 670476

African (AFR) AF: 0.00 AC: 0 AN: 28252

American (AMR) AF: 0.00 AC: 0 AN: 32132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23872

East Asian (EAS) AF: 0.000189 AC: 6 AN: 31734

South Asian (SAS) AF: 0.00 AC: 0 AN: 75544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058286

Other (OTH) AF: 0.00 AC: 0 AN: 55996

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151772 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74204

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000130 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73G>A (p.A25T) alteration is located in exon 1 (coding exon 1) of the SLC25A4 gene. This alteration results from a G to A substitution at nucleotide position 73, causing the alanine (A) at amino acid position 25 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the SLC25A4 protein (p.Ala25Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SLC25A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1967270). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A4 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.65
Sift	Benign	0.077	T
Sift4G	Benign	0.10	T
Polyphen		0.13	B
Vest4		0.42
MutPred		0.59		Gain of glycosylation at A25 (P = 0.0082);
MVP		0.84
MPC		1.9
ClinPred		0.50	T
GERP RS		5.0
PromoterAI		-0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.41
gMVP		0.75
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs560967545; hg19: chr4-186064599;