22-19176143-C-T

Variant names:

• chr22-19176143-C-T
• NM_005984.5:c.923G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_005984.5(SLC25A1):​c.923G>A​(p.Trp308*) variant causes a stop gained 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A1 NM_005984.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

Genes affected

SLC25A1 (HGNC:10979): (solute carrier family 25 member 1) This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0139 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A1	NM_005984.5	c.923G>A	p.Trp308*	stop_gained	Exon 9 of 9	ENST00000215882.10	NP_005975.1
SLC25A1	NM_001256534.2	c.944G>A	p.Trp315*	stop_gained	Exon 8 of 8		NP_001243463.1
SLC25A1	NM_001287387.2	c.614G>A	p.Trp205*	stop_gained	Exon 9 of 9		NP_001274316.1
SLC25A1	NR_046298.3	n.847G>A		non_coding_transcript_exon_variant	Exon 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A1	ENST00000215882.10	c.923G>A	p.Trp308*	stop_gained	Exon 9 of 9	1	NM_005984.5	ENSP00000215882.5
SLC25A1	ENST00000451283.5	c.614G>A	p.Trp205*	stop_gained	Exon 9 of 9	2		ENSP00000401480.1
SLC25A1	ENST00000470922.5	n.1065G>A		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC25A1 c.923G>A (p.Trp308X) results in a premature termination codon, predicted to cause a truncation of the encoded protein and not involved in NMD mechanism. The variant was absent in 251226 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.923G>A in individuals affected with Myasthenic Syndrome, Congenital, 23, Presynaptic and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.71
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19163656;