11-85650317-T-G

Position:

• chr11-85650317-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032273.4(TMEM126A):​c.62T>G​(p.Ile21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,455,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TMEM126A NM_032273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM126A	NM_032273.4	c.62T>G	p.Ile21Ser	missense_variant	2/5	ENST00000304511.7	NP_115649.1
TMEM126A	NM_001244735.2	c.-125+2228T>G		intron_variant			NP_001231664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM126A	ENST00000304511.7	c.62T>G	p.Ile21Ser	missense_variant	2/5	1	NM_032273.4	ENSP00000306887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250564 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1455582 Hom.: 0 Cov.: 28 AF XY: 0.00000966 AC XY: 7 AN XY: 724544

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1050336). This missense change has been observed in individual(s) with clinical features of TMEM126A-related conditions (PMID: 32855858). This variant is present in population databases (rs201584707, gnomAD 0.03%). This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the TMEM126A protein (p.Ile21Ser). -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TMEM126A p.Ile21Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs201584707) and in control databases in 5 of 250564 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 5 of 18362 chromosomes (freq: 0.000272), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Other or South Asian populations. The p.Ile21 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.27
Sift	Uncertain	0.011	D
Sift4G	Benign	0.065	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.64		Gain of disorder (P = 0.002);
MVP		0.54
MPC		0.20
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.38
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201584707; hg19: chr11-85361361;