rs141542003

Variant names:

• chr11-85636171-G-T
• rs141542003
• NM_018480.7:c.635G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_018480.7(TMEM126B):​c.635G>T​(p.Gly212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,605,814 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: TMEM126B NM_018480.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.44
• Publications: 21 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: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 11-85636171-G-T is Pathogenic according to our data. Variant chr11-85636171-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 236209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17585585). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000973 (148/152086) while in subpopulation NFE AF = 0.00178 (121/68028). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.635G>T	p.Gly212Val	missense	Exon 5 of 5	NP_060950.3
	TMEM126B	NM_001193537.3		c.575G>T	p.Gly192Val	missense	Exon 6 of 6	NP_001180466.1
	TMEM126B	NM_001193538.3		c.545G>T	p.Gly182Val	missense	Exon 6 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.635G>T	p.Gly212Val	missense	Exon 5 of 5	ENSP00000351737.7	Q8IUX1-1
	TMEM126B	ENST00000393375.5	TSL:1	c.545G>T	p.Gly182Val	missense	Exon 6 of 6	ENSP00000377039.1	Q8IUX1-5
	TMEM126B	ENST00000529197.1	TSL:1	n.*684G>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000436813.1	E9PKZ9

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 262 AN: 243948 AF XY: 0.00111

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00149 AC: 2159 AN: 1453728 Hom.: 3 Cov.: 31 AF XY: 0.00145 AC XY: 1046 AN XY: 723204

African (AFR) AF: 0.000151 AC: 5 AN: 33090

American (AMR) AF: 0.0000949 AC: 4 AN: 42164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.0000473 AC: 4 AN: 84570

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53176

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00182 AC: 2016 AN: 1109656

Other (OTH) AF: 0.000933 AC: 56 AN: 60046

GnomAD4 genome AF: 0.000973 AC: 148 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000875 AC XY: 65 AN XY: 74282

African (AFR) AF: 0.000338 AC: 14 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00128 AC: 156

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Mitochondrial complex I deficiency, nuclear type 29 (5)
4	-	-	not provided (5)
1	-	-	Mitochondrial complex I deficiency (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.33
MPC		0.29
ClinPred		0.097	T
GERP RS		4.1
Varity_R		0.59
gMVP		0.65
Mutation Taster		=32/68	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: rs141542003; hg19: chr11-85347215; COSMIC: COSV99074303; COSMIC: COSV99074303;