17-4937761-G-A

Variant names:

• chr17-4937761-G-A
• rs747131816
• NM_003562.5:c.925C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003562.5(SLC25A11):​c.925C>T​(p.Arg309Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,459,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SLC25A11 NM_003562.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

SLC25A11 (HGNC:10981): (solute carrier family 25 member 11) The oxoglutarate/malate carrier transports 2-oxoglutarate across the inner membranes of mitochondria in an electroneutral exchange for malate or other dicarboxylic acids (summary by Iacobazzi et al., 1992 [PubMed 1457818]).[supplied by OMIM, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37065578).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A11	NM_003562.5	c.925C>T	p.Arg309Cys	missense_variant	Exon 8 of 8	ENST00000225665.12	NP_003553.2
SLC25A11	NM_001165417.2	c.892C>T	p.Arg298Cys	missense_variant	Exon 8 of 8		NP_001158889.1
SLC25A11	NM_001165418.2	c.772C>T	p.Arg258Cys	missense_variant	Exon 7 of 7		NP_001158890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A11	ENST00000225665.12	c.925C>T	p.Arg309Cys	missense_variant	Exon 8 of 8	1	NM_003562.5	ENSP00000225665.7
SLC25A11	ENST00000544061.6	c.772C>T	p.Arg258Cys	missense_variant	Exon 7 of 7	3		ENSP00000440804.2
SLC25A11	ENST00000574710.1	n.1732C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2
SLC25A11	ENST00000576951.1	c.*2C>T		downstream_gene_variant		5		ENSP00000458993.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249226 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459688 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 726166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the SLC25A11 protein (p.Arg309Cys). This variant is present in population databases (rs747131816, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC25A11-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.0066	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.87	P;.
Vest4		0.32
MutPred		0.61		Loss of MoRF binding (P = 2e-04);.;
MVP		0.57
MPC		1.9
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.14
gMVP		0.87

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: rs747131816; hg19: chr17-4841056;