rs1801591

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. T171T) has been classified 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

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

multiple acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ETFA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.0736

AC:

18483

AN:

251282

AF XY:

0.0757

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 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

African (AFR)

AF:

0.0121

AC:

404

AN:

33474

American (AMR)

AF:

0.0327

AC:

1464

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

956

AN:

26126

East Asian (EAS)

AF:

0.0540

AC:

2144

AN:

39672

South Asian (SAS)

AF:

0.0659

AC:

5677

AN:

86198

European-Finnish (FIN)

AF:

0.130

AC:

6941

AN:

53412

Middle Eastern (MID)

AF:

0.0479

AC:

276

AN:

5766

European-Non Finnish (NFE)

AF:

0.0903

AC:

100237

AN:

1110436

Other (OTH)

AF:

0.0745

AC:

4495

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

4870

9740

14609

19479

24349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3556

7112

10668

14224

17780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0643

AC:

9790

AN:

152270

Hom.:

433

Cov.:

AF XY:

0.0663

AC XY:

4933

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0155

AC:

643

AN:

41576

American (AMR)

AF:

0.0422

AC:

645

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3472

East Asian (EAS)

AF:

0.0571

AC:

296

AN:

5180

South Asian (SAS)

AF:

0.0696

AC:

336

AN:

4830

European-Finnish (FIN)

AF:

0.132

AC:

1399

AN:

10600

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0910

AC:

6188

AN:

68000

Other (OTH)

AF:

0.0606

AC:

128

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

458

916

1374

1832

2290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0810

Hom.:

2226

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

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:3

Mar 08, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.;.;.

PhyloP100

9.5

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

Mutation Taster

=255/45

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over