rs1553253989

Positions:

• chr1-108157481-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. 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:6 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 16 ACMG points.

• 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 Lovd as [Pathogenic].
• 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/exons	MANE	Protein	UniProt
SLC25A24	NM_013386.5	c.650G>A	p.Arg217His	missense_variant	5/10	ENST00000565488.6	NP_037518.3
SLC25A24	NM_213651.3	c.593G>A	p.Arg198His	missense_variant	5/10		NP_998816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A24	ENST00000565488.6	c.650G>A	p.Arg217His	missense_variant	5/10	1	NM_013386.5	ENSP00000457733	P1
SLC25A24	ENST00000370041.4	c.593G>A	p.Arg198His	missense_variant	5/10	1		ENSP00000359058
SLC25A24	ENST00000648874.1	c.650G>A	p.Arg217His	missense_variant, NMD_transcript_variant	5/11			ENSP00000497117
SLC25A24	ENST00000264128.13	c.*229G>A		3_prime_UTR_variant, NMD_transcript_variant	4/9	5		ENSP00000264128

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fontaine progeroid syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 04, 2016	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

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;.
MutationTaster	Benign	1.0	D;D
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;