rs2196168

Variant names:

• chr11-85655718-A-G
• rs2196168
• NM_032273.4:c.395+10A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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: Benign. The variant received -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 VariationId is 262022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

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.395+10A>G		intron	N/A	NP_115649.1	Q9H061-1
	TMEM126A	NM_001244735.2		c.185+10A>G		intron	N/A	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.395+10A>G		intron	N/A	ENSP00000306887.2	Q9H061-1
	TMEM126A	ENST00000862988.1		c.395+10A>G		intron	N/A	ENSP00000533047.1
	TMEM126A	ENST00000862989.1		c.395+10A>G		intron	N/A	ENSP00000533048.1

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

GnomAD2 exomes AF: 0.290 AC: 72759 AN: 251040 AF XY: 0.284

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 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

African (AFR) AF: 0.398 AC: 13173 AN: 33088

American (AMR) AF: 0.418 AC: 18684 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6339 AN: 25986

East Asian (EAS) AF: 0.395 AC: 15625 AN: 39518

South Asian (SAS) AF: 0.384 AC: 32937 AN: 85812

European-Finnish (FIN) AF: 0.269 AC: 14364 AN: 53372

Middle Eastern (MID) AF: 0.224 AC: 1282 AN: 5722

European-Non Finnish (NFE) AF: 0.200 AC: 218947 AN: 1094066

Other (OTH) AF: 0.252 AC: 15015 AN: 59696

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

African (AFR) AF: 0.398 AC: 16512 AN: 41442

American (AMR) AF: 0.328 AC: 5007 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2016 AN: 5176

South Asian (SAS) AF: 0.397 AC: 1919 AN: 4828

European-Finnish (FIN) AF: 0.268 AC: 2832 AN: 10574

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13593 AN: 67948

Other (OTH) AF: 0.273 AC: 577 AN: 2110

Alfa AF: 0.253 Hom.: 1829

Bravo AF: 0.296

Asia WGS AF: 0.419 AC: 1457 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal recessive optic atrophy, OPA7 type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.74
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

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