NM_004453.4:c.3G>T

Variant names:

• chr4-158672459-G-T
• NM_004453.4:c.3G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004453.4(ETFDH):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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]

C4orf46 (HGNC:27320): (chromosome 4 open reading frame 46) This gene encodes a small, conserved protein of unknown function that is expressed in a variety of tissues. There are pseudogenes for this gene on chromosomes 6, 8, 16, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 62 codons. Genomic position: 158682203. Lost 0.099 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-158672459-G-T is Pathogenic according to our data. Variant chr4-158672459-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2746368.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETFDH	NM_004453.4	c.3G>T	p.Met1?	start_lost	Exon 1 of 13	ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2	c.3G>T	p.Met1?	start_lost	Exon 1 of 12		NP_001268666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETFDH	ENST00000511912.6	c.3G>T	p.Met1?	start_lost	Exon 1 of 13	1	NM_004453.4	ENSP00000426638.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Disruption of the initiator codon has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 24357026, 29336361, 35314173). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. For these reasons, this variant has been classified as Pathogenic. -

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
DEOGEN2	Benign	0.15	.;T;.
Eigen	Benign	-0.0063
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.64	D
PROVEAN	Uncertain	-4.0	D;N;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;.
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-159593611;