NM_000126.4:c.797C>T

Variant names:

• chr15-76274431-G-A
• rs119458970
• NM_000126.4:c.797C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000126.4(ETFA):​c.797C>T​(p.Thr266Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238819: Expression studies demonstrate a decrease in enzyme activity (Salazar et al., 1997)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T266T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ETFA NM_000126.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.35
• Publications: 14 publications found

Genes affected

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

ENSG00000287503 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238819: Expression studies demonstrate a decrease in enzyme activity (Salazar et al., 1997);; SCV002822200: PS3:Supporting; SCV000393968: Functional studies demonstrated that the p.Thr266Met variant protein showed an altered flavin environment and reduced enzyme activity (Salazar et. al. 1997). Fatty acid oxidation assays in patient fibroblasts showed the variant resulted in a severely defective beta-oxidation flux, with 3% to 26% of oxidation compared to controls (Freneaux et al. 1992; Olsen et. al. 2003).; SCV001227041: Experimental studies have shown that this missense change affects ETFA function (PMID: 9334218).; SCV003928794: Experimental evidence demonstrated the variant affects protein function (Salazar_1997, van Rijt_2019).; SCV004719155: The p.Thr266Met amino acid substitution has been reported to disrupt the FAD binding site, and results in a great decrease in ETF activity (Schiff et al. 2006. PubMed ID: 16510302; Henriques et al. 2010. PubMed ID: 20674745).; SCV006231859: Functional studies suggest a loss of function effect; however, additional evidence is needed to confirm these findings (Salazar, 1997; Augustin, 2018).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 15-76274431-G-A is Pathogenic according to our data. Variant chr15-76274431-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000126.4. 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
	ETFA	NM_000126.4	MANE Select	c.797C>T	p.Thr266Met	missense	Exon 9 of 12	NP_000117.1	P13804-1
	ETFA	NM_001127716.2		c.650C>T	p.Thr217Met	missense	Exon 8 of 11	NP_001121188.1	P13804-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFA	ENST00000557943.6	TSL:1 MANE Select	c.797C>T	p.Thr266Met	missense	Exon 9 of 12	ENSP00000452762.1	P13804-1
	ETFA	ENST00000560595.6	TSL:1	c.1016C>T	p.Thr339Met	missense	Exon 11 of 14	ENSP00000453345.2	H0YLU7
	ETFA	ENST00000692691.1		c.920C>T	p.Thr307Met	missense	Exon 10 of 13	ENSP00000508808.1	A0A8I5KVL5

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000444 AC: 11 AN: 247916 AF XY: 0.0000672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000715

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000603 AC: 88 AN: 1458926 Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 40 AN XY: 725508

African (AFR) AF: 0.0000897 AC: 3 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000739 AC: 82 AN: 1110318

Other (OTH) AF: 0.0000332 AC: 2 AN: 60268

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Multiple acyl-CoA dehydrogenase deficiency (7)
4	-	-	not provided (4)
1	-	-	ETFA-related disorder (1)
1	-	-	Glutaric acidemia IIa (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		9.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.98
MPC		1.2
ClinPred		0.92	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.86
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs119458970; hg19: chr15-76566772;