chr11-85631688-T-C

Position:

• chr11-85631688-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_018480.7(TMEM126B):​c.83T>C​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. V28V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: TMEM126B NM_018480.7 missense, splice_region
• Scores: Splicing: ADA: 0.00007934
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.861

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]

ACMG classification

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
TMEM126B	NM_018480.7	c.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
TMEM126B	ENST00000358867.11	c.83T>C	p.Val28Ala	missense_variant, splice_region_variant	2/5	2	NM_018480.7	P1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152078 Hom.: 1 Cov.: 33

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

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

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

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TMEM126B: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

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

Other links and lift over

dbSNP: rs115581134; hg19: chr11-85342732; COSMIC: COSV100729016; COSMIC: COSV100729016;