22-19176137-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005984.5(SLC25A1):c.929C>T(p.Thr310Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T310A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SLC25A1 NM_005984.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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.

• PM1: In a chain Tricarboxylate transport protein, mitochondrial (size 297) in uniprot entity TXTP_HUMAN there are 42 pathogenic changes around while only 0 benign (100%) in NM_005984.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A1	NM_005984.5	c.929C>T	p.Thr310Met	missense_variant	9/9	ENST00000215882.10
SLC25A1	NM_001256534.2	c.950C>T	p.Thr317Met	missense_variant	8/8
SLC25A1	NM_001287387.2	c.620C>T	p.Thr207Met	missense_variant	9/9
SLC25A1	NR_046298.3	n.853C>T		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A1	ENST00000215882.10	c.929C>T	p.Thr310Met	missense_variant	9/9	1	NM_005984.5	P1
SLC25A1	ENST00000451283.5	c.620C>T	p.Thr207Met	missense_variant	9/9	2
SLC25A1	ENST00000470922.5	n.1071C>T		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251156 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461266 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

This variant has not been reported in the literature in individuals affected with SLC25A1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs782723670, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 310 of the SLC25A1 protein (p.Thr310Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.31		Loss of methylation at K309 (P = 0.0301);.;
MVP		0.64
MPC		1.3
ClinPred		0.68	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.52

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: rs782723670; hg19: chr22-19163650; COSMIC: COSV53206243; COSMIC: COSV53206243;