Genetic Variant SLC25A11:p.Arg271His (chr17-4937874-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003562.5(SLC25A11):c.812G>A(p.Arg271His) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,614 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. R271C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SLC25A11
NM_003562.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

Variant links:

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]

SLC25A11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A11	NM_003562.5 link	c.812G>A	p.Arg271His	missense_variant	Exon 8 of 8	ENST00000225665.12	NP_003553.2	Q02978-1Q6IBH0
SLC25A11	NM_001165417.2 link	c.779G>A	p.Arg260His	missense_variant	Exon 8 of 8		NP_001158889.1	Q6IBH0
SLC25A11	NM_001165418.2 link	c.659G>A	p.Arg220His	missense_variant	Exon 7 of 7		NP_001158890.1	Q6IBH0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC25A11	ENST00000225665.12 link	c.812G>A	p.Arg271His	missense_variant	Exon 8 of 8	1	NM_003562.5	ENSP00000225665.7	Q02978-1
SLC25A11	ENST00000576951.1 link	c.779G>A	p.Arg260His	missense_variant	Exon 8 of 8	5		ENSP00000458993.1	I3L1P8
SLC25A11	ENST00000544061.6 link	c.659G>A	p.Arg220His	missense_variant	Exon 7 of 7	3		ENSP00000440804.2	Q02978-2
SLC25A11	ENST00000574710.1 link	n.1619G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250080

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135176

show subpopulations

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:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461308

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.812G>A (p.R271H) alteration is located in exon 8 (coding exon 8) of the SLC25A11 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the arginine (R) at amino acid position 271 to be replaced by a histidine (H). 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

Benign

0.18

BayesDel_addAF

Benign

0.0016

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.0

M;.;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0050

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.46

MVP

0.82

MPC

2.2

ClinPred

0.94

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over