chr4-158682269-G-A

Position:

chr4-158682269-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_004453.4(ETFDH):c.250G>A(p.Ala84Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,172 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ETFDH
NM_004453.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11U: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 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

PP5

Variant 4-158682269-G-A is Pathogenic according to our data. Variant chr4-158682269-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12028.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.250G>A	p.Ala84Thr	missense_variant	3/13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2 linkuse as main transcript	c.109G>A	p.Ala37Thr	missense_variant	2/12		NP_001268666.1
ETFDH	NM_001281738.1 linkuse as main transcript	c.67G>A	p.Ala23Thr	missense_variant	1/11		NP_001268667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6 linkuse as main transcript	c.250G>A	p.Ala84Thr	missense_variant	3/13	1	NM_004453.4	ENSP00000426638	P1	Q16134-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152172

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:

0.000578

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:

0.000135

AC:

AN:

251434

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 27, 2021	- -
Likely pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012028, PMID:19249206, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). A different missense change at the same codon has been reported to be associated with ETFDH related disorder (PMID:23628458, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.886, 3CNET: 0.925, PP3_P). A missense variant is a common mechanism associated with Glutaric acidemia IIC (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000127, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: ETFDH c.250G>A (p.Ala84Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ETFDH causing Glutaric Aciduria, Type 2c (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.250G>A has been reported in the literature in multiple individuals affected with lateonset multiple acylcoenzyme A dehydrogenation deficiency, including as a homozygote or heterozygote phenotype without second variants reported (e.g. Liu_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating an impact on protein function in Etfdh-(h)A84T knock-in mice, showing reduced protein levels in muscle and liver with vitamin B2 deficiency, and clinical and biochemical profiles similar to human patients affected with riboflavin-responsive multiple acylcoenzyme A dehydrogenation deficiency (e.g. Xu_2018). The following publications have been ascertained in the context of this evaluation (PMID: 27270537, 30232818). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 84 of the ETFDH protein (p.Ala84Thr). This variant is present in population databases (rs121964954, gnomAD 0.2%). This missense change has been observed in individuals with late-onset, riboflavine-responsive form of MADD (PMID: 19249206, 20370797, 21347544, 22013910, 24357026, 27000805, 27270537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12028). 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%. Experimental studies have shown that this missense change affects ETFDH function (PMID: 27935074). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2022	Functional studies in an A84T knock-in mouse model found this variant was associated with lower steady state levels of ETF:QO protein and increased acylcarnitine concentration in muscle that was riboflavin-dependent, consistent with findings in muscle cells from affected individuals (Xu J et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27060313, 20370797, 25119904, 24357026, 21347544, 22013910, 19249206, 27000805, 24522293, 19265687, 29961769, 29615056, 28950901, 31058673, 31852447, 32190638, 27935074, 32778825, 33639866, 32005694, 33589341, 29046209, 27270537, 30709034, 30232818) -

Glutaric acidemia IIc

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

See cases

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Pediatric Department, Xiangya Hospital, Central South University

This variant was observed in compound heterozygosity with variant (c.2T>G) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.99

MPC

0.47

ClinPred

0.91

GERP RS

6.0

Varity_R

0.94

gMVP

0.87

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