rs773668457

chr4-158680553-C-Gchr4-158680553-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004453.4(ETFDH):c.121C>G(p.Arg41Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETFDH NM_004453.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.33

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.121C>G	p.Arg41Gly	missense_variant	2/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.35-1642C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.121C>G	p.Arg41Gly	missense_variant	2/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.019	D
Polyphen		0.011	B
Vest4		0.66
MutPred		0.45		Loss of glycosylation at S37 (P = 0.02);
MVP		0.90
MPC		0.14
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.36
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs773668457; hg19: chr4-159601705;