rs761854400

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004453.4(ETFDH):c.841A>G(p.Ile281Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000996 in 1,607,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ETFDH
NM_004453.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.88

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15948334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ETFDH	NM_004453.4 linkuse as main transcript	c.841A>G	p.Ile281Val	missense_variant	8/13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2 linkuse as main transcript	c.700A>G	p.Ile234Val	missense_variant	7/12		NP_001268666.1
ETFDH	NM_001281738.1 linkuse as main transcript	c.658A>G	p.Ile220Val	missense_variant	6/11		NP_001268667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6 linkuse as main transcript	c.841A>G	p.Ile281Val	missense_variant	8/13	1	NM_004453.4	ENSP00000426638	P1	Q16134-1

Frequencies

GnomAD3 genomes

AF:

0.0000470

AC:

AN:

149022

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:

0.000104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000921

AC:

AN:

249800

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1458074

Hom.:

Cov.:

AF XY:

0.0000979

AC XY:

AN XY:

725378

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000307

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000470

AC:

AN:

149022

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

72520

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:

0.000104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 281 of the ETFDH protein (p.Ile281Val). 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. This variant has not been reported in the literature in individuals affected with ETFDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 529453). 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 not expected to disrupt ETFDH protein function. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.841A>G (p.I281V) alteration is located in exon 8 (coding exon 8) of the ETFDH gene. This alteration results from a A to G substitution at nucleotide position 841, causing the isoleucine (I) at amino acid position 281 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.20

T;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Uncertain

0.071

MutationAssessor

Benign

0.34

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.22

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.59

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

0.011

B;.;.

Vest4

0.38

MVP

0.90

MPC

0.081

ClinPred

0.076

GERP RS

5.5

Varity_R

0.096

gMVP

0.56

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

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