11-85631688-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_018480.7(TMEM126B):ā€‹c.83T>Cā€‹(p.Val28Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,607,026 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. V28V) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0027 ( 1 hom., cov: 33)
Exomes š‘“: 0.00024 ( 1 hom. )

Consequence

TMEM126B
NM_018480.7 missense, splice_region

Scores

18
Splicing: ADA: 0.00007934
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.861
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0031417608).
BP6
Variant 11-85631688-T-C is Benign according to our data. Variant chr11-85631688-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1202470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00269 (410/152196) while in subpopulation AFR AF= 0.00877 (364/41520). AF 95% confidence interval is 0.00802. There are 1 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TMEM126BNM_018480.7 linkuse as main transcriptc.83T>C p.Val28Ala missense_variant, splice_region_variant 2/5 ENST00000358867.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TMEM126BENST00000358867.11 linkuse as main transcriptc.83T>C p.Val28Ala missense_variant, splice_region_variant 2/52 NM_018480.7 P1Q8IUX1-1

Frequencies

GnomAD3 genomes
AF:
0.00269
AC:
409
AN:
152078
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00877
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
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:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000639
AC:
156
AN:
244132
Hom.:
2
AF XY:
0.000523
AC XY:
69
AN XY:
132020
show subpopulations
Gnomad AFR exome
AF:
0.00840
Gnomad AMR exome
AF:
0.000400
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000348
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000895
Gnomad OTH exome
AF:
0.00117
GnomAD4 exome
AF:
0.000236
AC:
344
AN:
1454830
Hom.:
1
Cov.:
31
AF XY:
0.000185
AC XY:
134
AN XY:
723536
show subpopulations
Gnomad4 AFR exome
AF:
0.00845
Gnomad4 AMR exome
AF:
0.000495
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:
0.00000360
Gnomad4 OTH exome
AF:
0.000632
GnomAD4 genome
AF:
0.00269
AC:
410
AN:
152196
Hom.:
1
Cov.:
33
AF XY:
0.00262
AC XY:
195
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.00877
Gnomad4 AMR
AF:
0.00288
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00106
Hom.:
0
Bravo
AF:
0.00334
ESP6500AA
AF:
0.00500
AC:
22
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000840
AC:
102
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 10, 2020- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023TMEM126B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
16
DANN
Benign
0.68
DEOGEN2
Benign
0.0047
T;.
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.20
T;T
MetaRNN
Benign
0.0031
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.18
N;N
REVEL
Benign
0.028
Sift
Benign
0.042
D;T
Sift4G
Benign
0.24
T;T
Vest4
0.20
MVP
0.13
MPC
0.041
ClinPred
0.0027
T
GERP RS
1.5
Varity_R
0.021
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000079
dbscSNV1_RF
Benign
0.0020
SpliceAI score (max)
0.060
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: rs115581134; hg19: chr11-85342732; COSMIC: COSV100729016; COSMIC: COSV100729016; API