NM_032273.4:c.163C>T

Variant names:

• chr11-85654139-C-T
• rs121434508
• NM_032273.4:c.163C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032273.4(TMEM126A):​c.163C>T​(p.Arg55*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TMEM126A NM_032273.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.71
• Publications: 20 publications found

Genes affected

TMEM126A (HGNC:25382): (transmembrane protein 126A) The protein encoded by this gene is a mitochondrial membrane protein of unknown function. Defects in this gene are a cause of optic atrophy type 7 (OPA7). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

TMEM126A Gene-Disease associations (from GenCC):

• autosomal recessive optic atrophy, OPA7 type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• optic atrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 11-85654139-C-T is Pathogenic according to our data. Variant chr11-85654139-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032273.4. 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
	TMEM126A	NM_032273.4	MANE Select	c.163C>T	p.Arg55*	stop_gained	Exon 3 of 5	NP_115649.1	Q9H061-1
	TMEM126A	NM_001244735.2		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001231664.1	Q9H061-2
	TMEM126A	NM_001244735.2		c.-48C>T		5_prime_UTR	Exon 2 of 4	NP_001231664.1	Q9H061-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM126A	ENST00000304511.7	TSL:1 MANE Select	c.163C>T	p.Arg55*	stop_gained	Exon 3 of 5	ENSP00000306887.2	Q9H061-1
	TMEM126A	ENST00000528105.5	TSL:2	c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000436590.1	Q9H061-2
	TMEM126A	ENST00000532180.1	TSL:3	c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	ENSP00000434357.1	Q9H061-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251482 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Autosomal recessive optic atrophy, OPA7 type (3)
1	-	-	TMEM126A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Benign	0.73	D
PhyloP100		1.7
Vest4		0.35
GERP RS		4.8
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: rs121434508; hg19: chr11-85365183; COSMIC: COSV58735100; COSMIC: COSV58735100;