19-43506795-C-A

Variant names:

• chr19-43506795-C-A
• rs201842186
• NM_014297.5:c.*55G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1 BS2

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
• Publications: 0 publications found

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]

ETHE1 Gene-Disease associations (from GenCC):

• ethylmalonic encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ETHE1	NM_014297.5	c.*55G>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000292147.7	NP_055112.2

Ensembl

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

African (AFR) AF: 0.000377 AC: 12 AN: 31860

American (AMR) AF: 0.000740 AC: 33 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 53 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.00735 AC: 622 AN: 84634

European-Finnish (FIN) AF: 0.00355 AC: 188 AN: 52908

Middle Eastern (MID) AF: 0.0146 AC: 65 AN: 4450

European-Non Finnish (NFE) AF: 0.00190 AC: 1982 AN: 1042944

Other (OTH) AF: 0.00258 AC: 149 AN: 57756

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

African (AFR) AF: 0.000481 AC: 20 AN: 41542

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4820

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2020

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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) -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.48
PhyloP100		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201842186; hg19: chr19-44010947;