19-43507763-T-C

Position:

• chr19-43507763-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP7 BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.712+181A>G variant in the ETHE1 gene is reported as >12% in gnomAD, including 167 homozygotes, which is high enough to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In silico splicing predictors (Splice AI) for this intronic variant do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA308740635/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.14 (903 hom., cov: 7)
  • Exomes 𝑓: 0.15 (4383 hom.)
• Consequence: ETHE1 ENST00000600651 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.118

Genes affected

ETHE1 (HGNC:23287): (ETHE1 persulfide dioxygenase) This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETHE1	NM_014297.5	c.712+181A>G		intron_variant		ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7	c.712+181A>G		intron_variant		1	NM_014297.5	ENSP00000292147.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 7279 AN: 51350 Hom.: 902 Cov.: 7

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0709

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.145 AC: 36073 AN: 248696 Hom.: 4383 Cov.: 4 AF XY: 0.142 AC XY: 19318 AN XY: 136020

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.0580

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.142 AC: 7281 AN: 51366 Hom.: 903 Cov.: 7 AF XY: 0.142 AC XY: 3406 AN XY: 23998

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0949

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0962

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.126

Alfa AF: 0.275 Hom.: 185

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ethylmalonic encephalopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 07, 2021

The allele frequency of the c.712+181A>G variant in the ETHE1 gene is reported as >12% in gnomAD, including 167 homozygotes, which is high enough to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In silico splicing predictors (Splice AI) for this intronic variant do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.80

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: rs12985024; hg19: chr19-44011915;