rs200111698

chr4-158706278-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_004453.4(ETFDH):c.1375C>T(p.His459Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,611,280 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H459H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: ETFDH NM_004453.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.91

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004453.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.059961468).
• BP6: Variant 4-158706278-C-T is Benign according to our data. Variant chr4-158706278-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203723.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETFDH	NM_004453.4	c.1375C>T	p.His459Tyr	missense_variant	11/13	ENST00000511912.6
ETFDH	NM_001281737.2	c.1234C>T	p.His412Tyr	missense_variant	10/12
ETFDH	NM_001281738.1	c.1192C>T	p.His398Tyr	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETFDH	ENST00000511912.6	c.1375C>T	p.His459Tyr	missense_variant	11/13	1	NM_004453.4	P1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152072 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000676 AC: 170 AN: 251354 Hom.: 2 AF XY: 0.000655 AC XY: 89 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1459090 Hom.: 3 Cov.: 29 AF XY: 0.000351 AC XY: 255 AN XY: 726094

Gnomad4 AFR exome AF: 0.0000299

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: 0.00588

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152190 Hom.: 1 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74410

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple acyl-CoA dehydrogenase deficiency Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 20, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2017

The H459Y missense change has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Database reports H459Y was observed in 2/186 (1.08%) alleles from individuals of Finnish background. The amino acid change is non-conservative in that a positively charged Histidine residue is replaced by an uncharged Tyrosine residue. This change occurs at a highly conserved position in the ETFDH protein, and multiple in-silico analysis models predict that H459Y is damaging to the ETFDH protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.056	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.93	P;.
Vest4		0.83
MVP		0.97
MPC		0.35
ClinPred		0.71	D
GERP RS		5.9
Varity_R		0.25
gMVP		0.87

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: rs200111698; hg19: chr4-159627430;