NM_032273.4:c.395+5G>A

Variant names:

• chr11-85655713-G-A
• rs115906592
• NM_032273.4:c.395+5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032273.4(TMEM126A):​c.395+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00116 in 1,601,568 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: TMEM126A NM_032273.4 splice_region, intron
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.01
• Publications: 1 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=-0.56).
• BP6: Variant 11-85655713-G-A is Benign according to our data. Variant chr11-85655713-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00619 (942/152230) while in subpopulation AFR AF = 0.0221 (917/41530). AF 95% confidence interval is 0.0209. There are 7 homozygotes in GnomAd4. There are 456 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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+5G>A		splice_region intron	N/A	NP_115649.1	Q9H061-1
	TMEM126A	NM_001244735.2		c.185+5G>A		splice_region 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+5G>A		splice_region intron	N/A	ENSP00000306887.2	Q9H061-1
	TMEM126A	ENST00000862988.1		c.395+5G>A		splice_region intron	N/A	ENSP00000533047.1
	TMEM126A	ENST00000862989.1		c.395+5G>A		splice_region intron	N/A	ENSP00000533048.1

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 940 AN: 152112 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00170 AC: 428 AN: 251166 AF XY: 0.00122

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000633 AC: 918 AN: 1449338 Hom.: 9 Cov.: 26 AF XY: 0.000518 AC XY: 374 AN XY: 721826

African (AFR) AF: 0.0236 AC: 782 AN: 33178

American (AMR) AF: 0.000850 AC: 38 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000263 AC: 29 AN: 1100838

Other (OTH) AF: 0.00112 AC: 67 AN: 59968

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152230 Hom.: 7 Cov.: 33 AF XY: 0.00613 AC XY: 456 AN XY: 74418

African (AFR) AF: 0.0221 AC: 917 AN: 41530

American (AMR) AF: 0.00105 AC: 16 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00329 Hom.: 9

Bravo AF: 0.00708

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive optic atrophy, OPA7 type (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.89
PhyloP100		5.0
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.13		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: rs115906592; hg19: chr11-85366757;