chr11-85631738-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018480.7(TMEM126B):ā€‹c.133G>Cā€‹(p.Asp45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TMEM126B
NM_018480.7 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
Variant links:
Genes affected
TMEM126B (HGNC:30883): (transmembrane protein 126B) This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TMEM126BNM_018480.7 linkuse as main transcriptc.133G>C p.Asp45His missense_variant 2/5 ENST00000358867.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TMEM126BENST00000358867.11 linkuse as main transcriptc.133G>C p.Asp45His missense_variant 2/52 NM_018480.7 P1Q8IUX1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461108
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726872
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 24, 2022In 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TMEM126B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 45 of the TMEM126B protein (p.Asp45His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.020
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.058
.;T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.66
D;D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.6
.;M;M
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.4
N;N;D
REVEL
Benign
0.21
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.0040
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.53
MutPred
0.63
.;Loss of ubiquitination at K47 (P = 0.0464);Loss of ubiquitination at K47 (P = 0.0464);
MVP
0.32
MPC
0.28
ClinPred
0.95
D
GERP RS
4.9
Varity_R
0.10
gMVP
0.60

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: chr11-85342782; API