4-158682400-C-G

Variant names:

• chr4-158682400-C-G
• NM_004453.4:c.381C>G
• ETFDH p.Leu127Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004453.4(ETFDH):​c.381C>G​(p.Leu127Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L127L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETFDH NM_004453.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819
• 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]

ETFDH Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=-0.819 with no splicing effect.

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.381C>G	p.Leu127Leu	synonymous	Exon 3 of 13	NP_004444.2	Q16134-1
	ETFDH	NM_001281737.2		c.240C>G	p.Leu80Leu	synonymous	Exon 2 of 12	NP_001268666.1	Q16134-3
	ETFDH	NM_001281738.1		c.198C>G	p.Leu66Leu	synonymous	Exon 1 of 11	NP_001268667.1	B4DEQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	ENST00000511912.6	TSL:1 MANE Select	c.381C>G	p.Leu127Leu	synonymous	Exon 3 of 13	ENSP00000426638.1	Q16134-1
	ETFDH	ENST00000506422.1	TSL:1	n.86+9910C>G		intron	N/A
	ETFDH	ENST00000684622.1		c.381C>G	p.Leu127Leu	synonymous	Exon 3 of 14	ENSP00000507546.1	A0A804HJK8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	5.7
DANN	Benign	0.84
PhyloP100		-0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-159603552;