NM_018480.7:c.208C>T

Variant names:

• chr11-85634090-C-T
• rs886037857
• NM_018480.7:c.208C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018480.7(TMEM126B):​c.208C>T​(p.Gln70*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM126B NM_018480.7 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.546
• Publications: 2 publications found

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]

TMEM126B Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 29

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-85634090-C-T is Pathogenic according to our data. Variant chr11-85634090-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253167.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018480.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM126B	NM_018480.7	MANE Select	c.208C>T	p.Gln70*	stop_gained	Exon 3 of 5	NP_060950.3
	TMEM126B	NM_001193537.3		c.148C>T	p.Gln50*	stop_gained	Exon 4 of 6	NP_001180466.1
	TMEM126B	NM_001193538.3		c.118C>T	p.Gln40*	stop_gained	Exon 4 of 6	NP_001180467.1	Q8IUX1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM126B	ENST00000358867.11	TSL:2 MANE Select	c.208C>T	p.Gln70*	stop_gained	Exon 3 of 5	ENSP00000351737.7	Q8IUX1-1
	TMEM126B	ENST00000393375.5	TSL:1	c.118C>T	p.Gln40*	stop_gained	Exon 4 of 6	ENSP00000377039.1	Q8IUX1-5
	TMEM126B	ENST00000528361.5	TSL:1	n.*257C>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000433444.1	E9PKZ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.0077	N
PhyloP100		0.55
Vest4		0.094
GERP RS		3.8
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037857; hg19: chr11-85345134; COSMIC: COSV100729018; COSMIC: COSV100729018;