17-4938405-C-T

Variant names:

• chr17-4938405-C-T
• NM_003562.5:c.571G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003562.5(SLC25A11):​c.571G>A​(p.Ala191Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC25A11 NM_003562.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A11	NM_003562.5	c.571G>A	p.Ala191Thr	missense_variant	Exon 5 of 8	ENST00000225665.12	NP_003553.2
SLC25A11	NM_001165417.2	c.538G>A	p.Ala180Thr	missense_variant	Exon 5 of 8		NP_001158889.1
SLC25A11	NM_001165418.2	c.418G>A	p.Ala140Thr	missense_variant	Exon 4 of 7		NP_001158890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A11	ENST00000225665.12	c.571G>A	p.Ala191Thr	missense_variant	Exon 5 of 8	1	NM_003562.5	ENSP00000225665.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571G>A (p.A191T) alteration is located in exon 5 (coding exon 5) of the SLC25A11 gene. This alteration results from a G to A substitution at nucleotide position 571, causing the alanine (A) at amino acid position 191 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.83
MutPred		0.61		Loss of methylation at R190 (P = 0.0858);.;.;
MVP		0.86
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.94

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: chr17-4841700;