15-76192068-C-G

Variant names:

• chr15-76192068-C-G
• rs768333397
• NM_152335.5:c.845C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152335.5(TMEM266):​c.845C>G​(p.Pro282Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000075 in 1,333,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P282L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: TMEM266 NM_152335.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54
• Publications: 0 publications found

Genes affected

TMEM266 (HGNC:26763): (transmembrane protein 266) Enables protein homodimerization activity. Predicted to be involved in transmembrane transport. Located in cytosol; dendrite; and plasma membrane. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ETFA (HGNC:3481): (electron transfer flavoprotein subunit alpha) ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ETFA Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22809845).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152335.5. 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
	TMEM266	NM_152335.5	MANE Select	c.845C>G	p.Pro282Arg	missense	Exon 9 of 11	NP_689548.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM266	ENST00000388942.9	TSL:5 MANE Select	c.845C>G	p.Pro282Arg	missense	Exon 9 of 11	ENSP00000373594.4
	TMEM266	ENST00000561302.6	TSL:1	n.*348C>G		non_coding_transcript_exon	Exon 8 of 11	ENSP00000453957.2	H0YNC9
	TMEM266	ENST00000561302.6	TSL:1	n.*348C>G		3_prime_UTR	Exon 8 of 11	ENSP00000453957.2	H0YNC9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333736 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 656064

African (AFR) AF: 0.00 AC: 0 AN: 26498

American (AMR) AF: 0.00 AC: 0 AN: 26566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21264

East Asian (EAS) AF: 0.00 AC: 0 AN: 30794

South Asian (SAS) AF: 0.00 AC: 0 AN: 70412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3810

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1055738

Other (OTH) AF: 0.00 AC: 0 AN: 54766

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0090	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.96	T
PhyloP100		4.5
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.088
Sift	Uncertain	0.019	D
Sift4G	Benign	0.23	T
Polyphen		0.85	P
Vest4		0.24
MutPred		0.29		Gain of MoRF binding (P = 0.0105)
MVP		0.81
MPC		0.77
ClinPred		0.64	D
GERP RS		3.4
Varity_R		0.11
gMVP		0.45
Mutation Taster		=86/14	polymorphism

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: rs768333397; hg19: chr15-76484409;