rs369711837

Positions:

chr4-158699098-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000511912.6(ETFDH):c.1084G>A(p.Gly362Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ETFDH
ENST00000511912.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ETFDH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000511912.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 4-158699098-G-A is Pathogenic according to our data. Variant chr4-158699098-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ETFDH	NM_004453.4 linkuse as main transcript	c.1084G>A	p.Gly362Arg	missense_variant	9/13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2 linkuse as main transcript	c.943G>A	p.Gly315Arg	missense_variant	8/12		NP_001268666.1
ETFDH	NM_001281738.1 linkuse as main transcript	c.901G>A	p.Gly301Arg	missense_variant	7/11		NP_001268667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6 linkuse as main transcript	c.1084G>A	p.Gly362Arg	missense_variant	9/13	1	NM_004453.4	ENSP00000426638	P1	Q16134-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251406

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135864

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000222

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 362 of the ETFDH protein (p.Gly362Arg). This variant is present in population databases (rs369711837, gnomAD 0.004%). This missense change has been observed in individual(s) with multiple acyl-CoA dehydrogenase deficiency or glutaric aciduria type II (PMID: 18289905, 19758981). ClinVar contains an entry for this variant (Variation ID: 459962). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETFDH protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2024	- -

ETFDH-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2023

The ETFDH c.1084G>A variant is predicted to result in the amino acid substitution p.Gly362Arg. This variant was reported in the compound heterozygous state in individuals who presented with suspected late-onset glutaric acidemia type 2 and ETFDH deficiency (Yotsumoto et al. 2008. PubMed ID: 18289905) or riboflavin-responsive lipid-storage myopathy (Wen et al. 2009. PubMed ID: 19758981). This variant was also described in the heterozygous state in an individual with multiple acyl-CoA dehydrogenase deficiency; however, a second plausible causative variant was not identified (Zhu et al. 2014. PubMed ID: 24522293). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-159620250-G-A). This variant is interpreted as likely pathogenic. -

Glutaric acidemia type 2C

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

1.0

MutPred

0.91

Gain of MoRF binding (P = 0.0165);.;

MVP

0.96

MPC

0.54

ClinPred

1.0

GERP RS

6.0

Varity_R

0.95

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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