rs878853082

Positions:

• chr4-158684648-C-G
• chr4-158684648-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004453.4(ETFDH):​c.462C>G​(p.Tyr154Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,460 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ETFDH NM_004453.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.356

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-158684648-C-G is Pathogenic according to our data. Variant chr4-158684648-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.462C>G	p.Tyr154Ter	stop_gained	4/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.321C>G	p.Tyr107Ter	stop_gained	3/12
ETFDH	NM_001281738.1	c.279C>G	p.Tyr93Ter	stop_gained	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.462C>G	p.Tyr154Ter	stop_gained	4/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421460 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 709794

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: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change creates a premature translational stop signal (p.Tyr154*) in the ETFDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFDH are known to be pathogenic (PMID: 16510302, 23785301). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ETFDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 235624). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs878853082; hg19: chr4-159605800;