chr19-43506795-C-A

Position:

• chr19-43506795-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.55G>T variant in the ETHE1 gene is >0.7% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10652049/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (14 hom.)
• Consequence: ETHE1 NM_014297.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 0.994

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 -12 ACMG points.

• 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.*55G>T		3_prime_UTR_variant	7/7	ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147	c.*55G>T		3_prime_UTR_variant	7/7	1	NM_014297.5	ENSP00000292147.1
ETHE1	ENST00000594342.5	n.*383G>T		non_coding_transcript_exon_variant	6/6	2		ENSP00000469652.1
ETHE1	ENST00000594342.5	n.*383G>T		3_prime_UTR_variant	6/6	2		ENSP00000469652.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152110 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00224 AC: 3104 AN: 1384064 Hom.: 14 Cov.: 22 AF XY: 0.00251 AC XY: 1738 AN XY: 692622

Gnomad4 AFR exome AF: 0.000377

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.00355

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152228 Hom.: 3 Cov.: 31 AF XY: 0.00148 AC XY: 110 AN XY: 74422

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Uncertain:2 Benign:1

Benign, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Aug 18, 2020	The filtering allele frequency of the c.55G>T variant in the ETHE1 gene is >0.7% by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Mito Variant Curation Expert Panel (BA1) -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs201842186; hg19: chr19-44010947;