17-4937874-C-T

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

6
9
4

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]

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
SLC25A11NM_003562.5 linkc.812G>A p.Arg271His missense_variant Exon 8 of 8 ENST00000225665.12 NP_003553.2 Q02978-1Q6IBH0
SLC25A11NM_001165417.2 linkc.779G>A p.Arg260His missense_variant Exon 8 of 8 NP_001158889.1 Q6IBH0
SLC25A11NM_001165418.2 linkc.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 Appris UniProt
SLC25A11ENST00000225665.12 linkc.812G>A p.Arg271His missense_variant Exon 8 of 8 1 NM_003562.5 ENSP00000225665.7 Q02978-1
SLC25A11ENST00000576951.1 linkc.779G>A p.Arg260His missense_variant Exon 8 of 8 5 ENSP00000458993.1 I3L1P8
SLC25A11ENST00000544061.6 linkc.659G>A p.Arg220His missense_variant Exon 7 of 7 3 ENSP00000440804.2 Q02978-2
SLC25A11ENST00000574710.1 linkn.1619G>A non_coding_transcript_exon_variant Exon 6 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
33
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:
4
AN:
250080
Hom.:
0
AF XY:
0.0000222
AC XY:
3
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:
8
AN:
1461308
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
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:
1
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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:
1

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
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.65
D;.;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.090
D
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Pathogenic
3.0
M;.;.
PrimateAI
Benign
0.41
T
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
D
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.

Other links and lift over

dbSNP: rs149333609; hg19: chr17-4841169; COSMIC: COSV52590882; COSMIC: COSV52590882; API