rs1553253990

Positions:

• chr1-108157482-G-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.649C>T​(p.Arg217Cys) variant causes a missense change. 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. R217H) 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:3
• Conservation: PhyloP100: 4.03

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 chr1-108157481-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 1-108157482-G-A is Pathogenic according to our data. 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. Variant chr1-108157482-G-A is described in UniProt as null. Variant chr1-108157482-G-A is described in Lovd as [Pathogenic]. Variant chr1-108157482-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A24	NM_013386.5	c.649C>T	p.Arg217Cys	missense_variant	5/10	ENST00000565488.6
SLC25A24	NM_213651.3	c.592C>T	p.Arg198Cys	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A24	ENST00000565488.6	c.649C>T	p.Arg217Cys	missense_variant	5/10	1	NM_013386.5	P1
SLC25A24	ENST00000370041.4	c.592C>T	p.Arg198Cys	missense_variant	5/10	1
SLC25A24	ENST00000648874.1	c.649C>T	p.Arg217Cys	missense_variant, NMD_transcript_variant	5/11
SLC25A24	ENST00000264128.13	c.*228C>T		3_prime_UTR_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fontaine progeroid syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	-	The de novo variant was identified at the same protein position as the variant reported as de novo in three independent cases with Petty syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.6	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.80		Loss of MoRF binding (P = 0.0205);.;
MVP		0.92
MPC		0.89
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.93

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: rs1553253990; hg19: chr1-108700104;