NM_013386.5:c.650G>A

Variant names:

• chr1-108157481-C-T
• rs1553253989
• NM_013386.5:c.650G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_013386.5(SLC25A24):​c.650G>A​(p.Arg217His) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A24 NM_013386.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.83

Genes affected

SLC25A24 (HGNC:20662): (solute carrier family 25 member 24) This gene encodes a carrier protein that transports ATP-Mg exchanging it for phosphate. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Mitochondrial matrix (size 36) in uniprot entity SCMC1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_013386.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-108157482-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 369980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 1-108157481-C-T is Pathogenic according to our data. Variant chr1-108157481-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 370032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-108157481-C-T is described in UniProt as null. Variant chr1-108157481-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A24	NM_013386.5	c.650G>A	p.Arg217His	missense_variant	Exon 5 of 10	ENST00000565488.6	NP_037518.3
SLC25A24	NM_213651.3	c.593G>A	p.Arg198His	missense_variant	Exon 5 of 10		NP_998816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A24	ENST00000565488.6	c.650G>A	p.Arg217His	missense_variant	Exon 5 of 10	1	NM_013386.5	ENSP00000457733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 04, 2024

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 217 of the SLC25A24 protein (p.Arg217His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fontaine progeroid syndrome (PMID: 29100094, 30329211). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 370032). 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 expected to disrupt SLC25A24 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC25A24 function (PMID: 29100094). For these reasons, this variant has been classified as Pathogenic. -

Jun 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest that this variant results in mitochondrial dysfunction (PMID: 29100093, 29100094); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30329211, 30281880, 29100093, 29100094, 21216154, 19731360, 10594888, 31775791, 31231135, 36093452, Pannier2022[Abstract], 37449547, 36647814) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 08-17-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Fontaine progeroid syndrome Pathogenic:3

Oct 11, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 04, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant was identified as de novo in three independent cases with the syndrome and functional studies have shown a likely altered function of the protein. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.81		Loss of MoRF binding (P = 0.0329);.;
MVP		0.84
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.83
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1553253989; hg19: chr1-108700103;