11-85628672-C-T

Position:

• chr11-85628672-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018480.7(TMEM126B):​c.65C>T​(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM126B NM_018480.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.340

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07807988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM126B	NM_018480.7	c.65C>T	p.Thr22Ile	missense_variant	1/5	ENST00000358867.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM126B	ENST00000358867.11	c.65C>T	p.Thr22Ile	missense_variant	1/5	2	NM_018480.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

The c.65C>T (p.T22I) alteration is located in exon 1 (coding exon 1) of the TMEM126B gene. This alteration results from a C to T substitution at nucleotide position 65, causing the threonine (T) at amino acid position 22 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.045
Sift	Benign	0.075	T;T
Sift4G	Uncertain	0.023	D;D
Vest4		0.076
MutPred		0.19		Loss of glycosylation at T22 (P = 0.0192);Loss of glycosylation at T22 (P = 0.0192);
MVP		0.21
MPC		0.039
ClinPred		0.22	T
GERP RS		0.80
Varity_R		0.047
gMVP		0.21

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

Other links and lift over

dbSNP: rs1004531835; hg19: chr11-85339716;