4-158672459-G-C

Position:

• chr4-158672459-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_004453.4(ETFDH):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETFDH NM_004453.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004453.4 (ETFDH) was described as [Pathogenic] in ClinVar as 2746368
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-158672459-G-C is Pathogenic according to our data. Variant chr4-158672459-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2203581.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.3G>C	p.Met1?	start_lost	1/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.3G>C	p.Met1?	start_lost	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.3G>C	p.Met1?	start_lost	1/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ETFDH protein in which other variant(s) (p.Pro27Ser) have been determined to be pathogenic (PMID: 3126856, 20023066, 27038534; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 24357026, 29336361). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ETFDH mRNA. The next in-frame methionine is located at codon 62. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.0063
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-4.0	D;N;N
REVEL	Uncertain	0.57
Polyphen		0.0080	.;B;.
Vest4		0.89, 0.92
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0442);Gain of catalytic residue at M1 (P = 0.0442);Gain of catalytic residue at M1 (P = 0.0442);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.55

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

Other links and lift over

dbSNP: rs1340862175; hg19: chr4-159593611;