NM_018480.7:c.401delA

Variant names:

• chr11-85635668-TA-T
• rs886037835
• NM_018480.7:c.401delA

Variant summary

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

The NM_018480.7(TMEM126B):​c.401delA​(p.Asn134IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 1,451,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: TMEM126B NM_018480.7 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.730
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 11-85635668-TA-T is Pathogenic according to our data. Variant chr11-85635668-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 236208.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM126B	NM_018480.7	c.401delA	p.Asn134IlefsTer2	frameshift_variant	Exon 4 of 5	ENST00000358867.11	NP_060950.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM126B	ENST00000358867.11	c.401delA	p.Asn134IlefsTer2	frameshift_variant	Exon 4 of 5	2	NM_018480.7	ENSP00000351737.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000896 AC: 13 AN: 1451394 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 721992

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 41774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 83798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108610

Other (OTH) AF: 0.00 AC: 0 AN: 59912

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 29 Pathogenic:1

Dec 13, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

May 18, 2016

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=10/190	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: rs886037835; hg19: chr11-85346712;