rs2196168

Positions:

• chr11-85655718-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032273.4(TMEM126A):​c.395+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,593,950 control chromosomes in the GnomAD database, including 50,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6837 hom., cov: 33)
  • Exomes 𝑓: 0.23 (43564 hom.)
• Consequence: TMEM126A NM_032273.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0600

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-85655718-A-G is Benign according to our data. Variant chr11-85655718-A-G is described in ClinVar as [Benign]. Clinvar id is 262022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-85655718-A-G is described in Lovd as [Likely_benign]. Variant chr11-85655718-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM126A	NM_032273.4	c.395+10A>G		intron_variant		ENST00000304511.7	NP_115649.1
TMEM126A	NM_001244735.2	c.185+10A>G		intron_variant			NP_001231664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM126A	ENST00000304511.7	c.395+10A>G		intron_variant		1	NM_032273.4	ENSP00000306887	P1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43388 AN: 151912 Hom.: 6796 Cov.: 33

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.272

GnomAD3 exomes AF: 0.290 AC: 72759 AN: 251040 Hom.: 11956 AF XY: 0.284 AC XY: 38483 AN XY: 135690

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.390

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.233 AC: 336366 AN: 1441918 Hom.: 43564 Cov.: 26 AF XY: 0.237 AC XY: 170121 AN XY: 718714

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.286 AC: 43487 AN: 152032 Hom.: 6837 Cov.: 33 AF XY: 0.294 AC XY: 21863 AN XY: 74318

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.273

Alfa AF: 0.251 Hom.: 1770

Bravo AF: 0.296

Asia WGS AF: 0.419 AC: 1457 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive optic atrophy, OPA7 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs2196168; hg19: chr11-85366762; COSMIC: COSV52629142; COSMIC: COSV52629142;