rs141407224

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_004453.4(ETFDH):​c.679C>A​(p.Pro227Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,554,770 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ETFDH
NM_004453.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 7.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
Variant 4-158690420-C-A is Pathogenic according to our data. Variant chr4-158690420-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ETFDHNM_004453.4 linkc.679C>A p.Pro227Thr missense_variant Exon 6 of 13 ENST00000511912.6 NP_004444.2 Q16134-1B4DEQ0
ETFDHNM_001281737.2 linkc.538C>A p.Pro180Thr missense_variant Exon 5 of 12 NP_001268666.1 Q16134-3B4DEQ0
ETFDHNM_001281738.1 linkc.496C>A p.Pro166Thr missense_variant Exon 4 of 11 NP_001268667.1 B4DEQ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ETFDHENST00000511912.6 linkc.679C>A p.Pro227Thr missense_variant Exon 6 of 13 1 NM_004453.4 ENSP00000426638.1 Q16134-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
30
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:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251428
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135888
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:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
23
AN:
1402792
Hom.:
0
Cov.:
24
AF XY:
0.0000200
AC XY:
14
AN XY:
701394
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:
0.0000588
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000123
Gnomad4 OTH exome
AF:
0.0000685
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
74216
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:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:1
Nov 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 227 of the ETFDH protein (p.Pro227Thr). This variant is present in population databases (rs141407224, gnomAD 0.006%). This missense change has been observed in individuals with glutaric aciduria (PMID: 34066864; internal data). ClinVar contains an entry for this variant (Variation ID: 459966). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Apr 21, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 23, 2024
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant has been reported pathogenic (PS1, Ali et al. 2021, PMID: 34066864). The variant causes functional damage (PS3, clinical/biochemical evidence). The variant is rare in the healthy population (PM2 - supporting). The variant is homozygous (PM3-supporting according to the ClinGen Sequence variant interpretation Recommendation for in-trans Criterion (PM3) - Version 1.0) -

Mar 19, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ETFDH: PM2, PM3, PM5, PP4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D;T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.91
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-7.5
D;D;D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.80
MVP
0.99
MPC
0.53
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.78
gMVP
0.75

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.

Other links and lift over

dbSNP: rs141407224; hg19: chr4-159611572; API