NM_004453.4:c.20_21delAGinsC

Variant names:

• chr4-158672476-AG-C
• NM_004453.4:c.20_21delAGinsC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_004453.4(ETFDH):​c.20_21delAGinsC​(p.Lys7ThrfsTer13) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K7N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETFDH NM_004453.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.06
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 268 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.39306 (below the threshold of 3.09). Trascript score misZ: 0.49505 (below the threshold of 3.09). GenCC associations: The gene is linked to multiple acyl-CoA dehydrogenase deficiency.
• PP5: Variant 4-158672476-AG-C is Pathogenic according to our data. Variant chr4-158672476-AG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3590423.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004453.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	NM_004453.4	MANE Select	c.20_21delAGinsC	p.Lys7ThrfsTer13	frameshift missense	Exon 1 of 13	NP_004444.2	Q16134-1
	ETFDH	NM_001281737.2		c.20_21delAGinsC	p.Lys7ThrfsTer7	frameshift missense	Exon 1 of 12	NP_001268666.1	Q16134-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	ENST00000511912.6	TSL:1 MANE Select	c.20_21delAGinsC	p.Lys7ThrfsTer13	frameshift missense	Exon 1 of 13	ENSP00000426638.1	Q16134-1
	ETFDH	ENST00000506422.1	TSL:1	n.72_73delAGinsC		non_coding_transcript_exon	Exon 1 of 5
	ETFDH	ENST00000510353.5	TSL:1	n.161_162delAGinsC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

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

Other links and lift over

hg19: chr4-159593628;