1-108136814-G-T

Position:

• chr1-108136814-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013386.5(SLC25A24):​c.1273C>A​(p.Leu425Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A24 NM_013386.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.600

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07046285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A24	NM_013386.5	c.1273C>A	p.Leu425Met	missense_variant	10/10	ENST00000565488.6
SLC25A24	NM_213651.3	c.1216C>A	p.Leu406Met	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A24	ENST00000565488.6	c.1273C>A	p.Leu425Met	missense_variant	10/10	1	NM_013386.5	P1
SLC25A24	ENST00000370041.4	c.1216C>A	p.Leu406Met	missense_variant	10/10	1
SLC25A24	ENST00000264128.13	c.*852C>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	5
SLC25A24	ENST00000648874.1	c.*594C>A		3_prime_UTR_variant, NMD_transcript_variant	11/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral tonic-clonic seizure;C0497327:Dementia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Research Unit for Rare Diseases, 1st Faculty of Medicine, Charles University in Prague

Sep 06, 2019

The Leu425Met variant in SLC25A24 has been reported in 1 large Belgian family with autosomal dominant inheritance of dementia, segregated with the disease exclusively in combination with another SLC25A24 variant Gly253Ala in cis configuration and a C9ORF72 hexanucelotide repeat expansion. And, it was absent from large population studies. Additionally, in vitro functional studies indicated, that the Gly253Ala variant reduced transport activity of the SLC25A24 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.33	N;N
Sift	Benign	0.19	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0060	B;B
Vest4		0.093
MutPred		0.28		Gain of MoRF binding (P = 0.0696);.;
MVP		0.57
MPC		0.21
ClinPred		0.091	T
GERP RS		0.058
Varity_R		0.056
gMVP		0.36

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: rs780069314; hg19: chr1-108679436;