15-76203990-C-A

Variant names:

• chr15-76203990-C-A
• rs771706401
• ENST00000388942.8:c.1271C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000388942.8(TMEM266):​c.1271C>A​(p.Pro424His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM266 ENST00000388942.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.830

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10670975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM266	NM_152335.5	c.1247C>A	p.Pro416His	missense_variant	Exon 11 of 11		NP_689548.3
TMEM266	XM_017021915.2	c.1271C>A	p.Pro424His	missense_variant	Exon 13 of 13		XP_016877404.1
TMEM266	XM_047432151.1	c.1271C>A	p.Pro424His	missense_variant	Exon 13 of 13		XP_047288107.1
TMEM266	XM_005254160.4	c.719C>A	p.Pro240His	missense_variant	Exon 9 of 9		XP_005254217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000388942.8	c.1271C>A	p.Pro424His	missense_variant	Exon 11 of 11	5	NM_152335.3	ENSP00000373594.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244686 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 6.87e-7 AC: 1 AN: 1456288 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 723464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1271C>A (p.P424H) alteration is located in exon 11 (coding exon 10) of the TMEM266 gene. This alteration results from a C to A substitution at nucleotide position 1271, causing the proline (P) at amino acid position 424 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.8
DANN	Benign	0.18
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.054
Sift	Benign	0.29	T
Sift4G	Uncertain	0.023	D
Polyphen		0.32	B
Vest4		0.25
MutPred		0.19		Loss of glycosylation at P424 (P = 0.0079);
MVP		0.46
MPC		0.40
ClinPred		0.27	T
GERP RS		1.7
Varity_R		0.055
gMVP		0.13

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: rs771706401; hg19: chr15-76496331;