rs1801591

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_000126.4(ETFA):c.512C>T(p.Thr171Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,612,408 control chromosomes in the GnomAD database, including 6,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 433 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5685 hom. )

Consequence

ETFA
NM_000126.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.004926473).

BP6

Variant 15-76286421-G-A is Benign according to our data. Variant chr15-76286421-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-76286421-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETFA	NM_000126.4 link	c.512C>T	p.Thr171Ile	missense_variant	Exon 6 of 12	ENST00000557943.6	NP_000117.1	P13804-1A0A0S2Z3L0
ETFA	NM_001127716.2 link	c.365C>T	p.Thr122Ile	missense_variant	Exon 5 of 11		NP_001121188.1	P13804-2
ETFA	XR_007064434.1 link	n.593C>T		non_coding_transcript_exon_variant	Exon 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFA	ENST00000557943.6 link	c.512C>T	p.Thr171Ile	missense_variant	Exon 6 of 12	1	NM_000126.4	ENSP00000452762.1		P13804-1

Frequencies

GnomAD3 genomes

AF:

0.0643

AC:

9783

AN:

152150

Hom.:

433

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0422

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.0578

Gnomad SAS

AF:

0.0691

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0910

Gnomad OTH

AF:

0.0569

GnomAD3 exomes

AF:

0.0736

AC:

18483

AN:

251282

Hom.:

810

AF XY:

0.0757

AC XY:

10285

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.0325

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.0552

Gnomad SAS exome

AF:

0.0675

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.0907

Gnomad OTH exome

AF:

0.0812

GnomAD4 exome

AF:

0.0840

AC:

122594

AN:

1460138

Hom.:

5685

Cov.:

AF XY:

0.0837

AC XY:

60798

AN XY:

726474

show subpopulations

Gnomad4 AFR exome

AF:

0.0121

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0366

Gnomad4 EAS exome

AF:

0.0540

Gnomad4 SAS exome

AF:

0.0659

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.0903

Gnomad4 OTH exome

AF:

0.0745

GnomAD4 genome

AF:

0.0643

AC:

9790

AN:

152270

Hom.:

433

Cov.:

AF XY:

0.0663

AC XY:

4933

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0422

Gnomad4 ASJ

AF:

0.0383

Gnomad4 EAS

AF:

0.0571

Gnomad4 SAS

AF:

0.0696

Gnomad4 FIN

AF:

0.132

Gnomad4 NFE

AF:

0.0910

Gnomad4 OTH

AF:

0.0606

Alfa

AF:

0.0826

Hom.:

1152

Bravo

AF:

0.0538

TwinsUK

AF:

0.0920

AC:

341

ALSPAC

AF:

0.0851

AC:

328

ESP6500AA

AF:

0.0171

AC:

ESP6500EA

AF:

0.0857

AC:

736

ExAC

AF:

0.0761

AC:

9241

Asia WGS

AF:

0.0720

AC:

253

AN:

3478

EpiCase

AF:

0.0806

EpiControl

AF:

0.0763

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 05, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;.;.;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.9

D;D;D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.45

MPC

1.2

ClinPred

0.12

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over