rs727503918

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000126.4(ETFA):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000448 in 1,563,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

ETFA
NM_000126.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.27

Publications

1 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:

ENSG00000299002 (HGNC:):

ENSG00000299002 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 53 pathogenic variants. Next in-frame start position is after 261 codons. Genomic position: 76274447. Lost 0.779 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-76311387-A-G is Pathogenic according to our data. Variant chr15-76311387-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167039.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ETFA	NM_000126.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 12	ENST00000557943.6	NP_000117.1
ETFA	NM_001127716.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11		NP_001121188.1
ETFA	XR_007064434.1 link	n.83T>C		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFA	ENST00000557943.6 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 12	1	NM_000126.4	ENSP00000452762.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000247

AC:

AN:

161802

AF XY:

0.0000456

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:

0.00

Gnomad NFE exome

AF:

0.0000633

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000482

AC:

AN:

1410828

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

697138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32408

American (AMR)

AF:

0.00

AC:

AN:

37558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25266

East Asian (EAS)

AF:

0.00

AC:

AN:

37084

South Asian (SAS)

AF:

0.00

AC:

AN:

80246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.0000607

AC:

AN:

1086772

Other (OTH)

AF:

0.0000342

AC:

AN:

58474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000310

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000175

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:2Uncertain:1

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the ETFA mRNA. The next in-frame methionine is located at codon 261. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individual(s) with glutaric aciduria type 2 (PMID: 33768790). ClinVar contains an entry for this variant (Variation ID: 167039). This variant disrupts a region of the ETFA protein in which other variant(s) (p.Arg122Lys) have been observed in individuals with ETFA-related conditions (PMID: 16510302). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Aug 09, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease -

Jan 17, 2014

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.12

T;.;.;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.29

PhyloP100

3.3

PROVEAN

Benign

-0.90

N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

0.0070

B;.;.;.;.

Vest4

0.92

MutPred

0.99

Gain of phosphorylation at M1 (P = 0.0096);Gain of phosphorylation at M1 (P = 0.0096);Gain of phosphorylation at M1 (P = 0.0096);Gain of phosphorylation at M1 (P = 0.0096);Gain of phosphorylation at M1 (P = 0.0096);

MVP

0.98

ClinPred

0.98

GERP RS

3.4

PromoterAI

-0.28

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.90

gMVP

0.78

Mutation Taster

=6/194

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over