11-85631730-C-T

Position:

• chr11-85631730-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018480.7(TMEM126B):​c.125C>T​(p.Ser42Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,336 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: TMEM126B NM_018480.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.183

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048446953).
• BP6: Variant 11-85631730-C-T is Benign according to our data. Variant chr11-85631730-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1203741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000291 (425/1461118) while in subpopulation MID AF= 0.00729 (42/5762). AF 95% confidence interval is 0.00554. There are 2 homozygotes in gnomad4_exome. There are 226 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM126B	NM_018480.7	c.125C>T	p.Ser42Phe	missense_variant	2/5	ENST00000358867.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM126B	ENST00000358867.11	c.125C>T	p.Ser42Phe	missense_variant	2/5	2	NM_018480.7	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152100 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000399 AC: 100 AN: 250628 Hom.: 0 AF XY: 0.000421 AC XY: 57 AN XY: 135524

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000291 AC: 425 AN: 1461118 Hom.: 2 Cov.: 31 AF XY: 0.000311 AC XY: 226 AN XY: 726884

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00548

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74416

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000527 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000655

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	See Variant Classification Assertion Criteria. -

TMEM126B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.2
DANN	Benign	0.38
DEOGEN2	Benign	0.019	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.096	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.053	.;B;.
Vest4		0.30
MVP		0.10
MPC		0.041
ClinPred		0.0012	T
GERP RS		1.9
Varity_R		0.029
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs143403924; hg19: chr11-85342774;