rs1553253989

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000320993: 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." and additional evidence is available in ClinVar. 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
• Publications: 6 publications found

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]

SLC25A24 Gene-Disease associations (from GenCC):

• Fontaine progeroid syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000320993: 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.; SCV002097451: Published functional studies suggest that this variant results in mitochondrial dysfunction (PMID: 29100093, 29100094); SCV005833986: Experimental studies have shown that this missense change affects SLC25A24 function (PMID: 29100094).
• 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 VariationId 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 VariationId is 370032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013386.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A24	NM_013386.5	MANE Select	c.650G>A	p.Arg217His	missense	Exon 5 of 10	NP_037518.3
	SLC25A24	NM_213651.3		c.593G>A	p.Arg198His	missense	Exon 5 of 10	NP_998816.1	Q6NUK1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A24	ENST00000565488.6	TSL:1 MANE Select	c.650G>A	p.Arg217His	missense	Exon 5 of 10	ENSP00000457733.1	Q6NUK1-1
	SLC25A24	ENST00000370041.4	TSL:1	c.593G>A	p.Arg198His	missense	Exon 5 of 10	ENSP00000359058.4	Q6NUK1-2
	SLC25A24	ENST00000948782.1		c.650G>A	p.Arg217His	missense	Exon 5 of 11	ENSP00000618841.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (5)
3	-	-	Fontaine progeroid syndrome (3)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	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
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs1553253989; hg19: chr1-108700103; COSMIC: COSV108761759;