rs557160401

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_000126.4(ETFA):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,562,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

ETFA
NM_000126.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.842

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ETFA links:

ENSG00000299002 (HGNC:):

ENSG00000299002 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005465746).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/152360) while in subpopulation NFE AF = 0.000544 (37/68038). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.20C>T	p.Pro7Leu	missense	Exon 1 of 12	NP_000117.1	P13804-1
	ETFA	NM_001127716.2		c.20C>T	p.Pro7Leu	missense	Exon 1 of 11	NP_001121188.1	P13804-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ETFA	ENST00000557943.6	TSL:1 MANE Select	c.20C>T	p.Pro7Leu	missense	Exon 1 of 12	ENSP00000452762.1	P13804-1
ETFA	ENST00000560595.6	TSL:1	c.20C>T	p.Pro7Leu	missense	Exon 1 of 14	ENSP00000453345.2	H0YLU7
ETFA	ENST00000560726.5	TSL:3	c.-532C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000453098.1	H0YL83

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000187

AC:

AN:

160244

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000134

Gnomad NFE exome

AF:

0.000421

Gnomad OTH exome

AF:

0.000448

GnomAD4 exome

AF:

0.000427

AC:

602

AN:

1409962

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

300

AN XY:

696648

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

32358

American (AMR)

AF:

0.0000534

AC:

AN:

37456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25250

East Asian (EAS)

AF:

0.00

AC:

AN:

36948

South Asian (SAS)

AF:

0.00

AC:

AN:

80208

European-Finnish (FIN)

AF:

0.0000837

AC:

AN:

47770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.000529

AC:

575

AN:

1086104

Other (OTH)

AF:

0.000291

AC:

AN:

58434

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000263

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000273

Hom.:

Bravo

AF:

0.000264

ExAC

AF:

0.000106

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple acyl-CoA dehydrogenase deficiency (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.55

MutationAssessor

Benign

-0.69

PhyloP100

0.84

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.65

REVEL

Benign

0.15

Sift

Uncertain

0.0070

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.29

MVP

0.79

MPC

0.37

ClinPred

0.17

GERP RS

2.5

PromoterAI

-0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.082

gMVP

0.32

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over