rs3810381

Positions:

• chr19-43527172-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.6G>A variant in the ETHE1 gene is reported as >16% in gnomAD, including >2,000 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) 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/CA9487981/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.17 (2401 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25246 hom.)
• Consequence: ETHE1 NM_014297.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: -1.84

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]

ZNF575 (HGNC:27606): (zinc finger protein 575) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETHE1	NM_014297.5	c.6G>A	p.Ala2=	synonymous_variant	1/7	ENST00000292147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETHE1	ENST00000292147.7	c.6G>A	p.Ala2=	synonymous_variant	1/7	1	NM_014297.5	P1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26481 AN: 152186 Hom.: 2401 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.157 AC: 20954 AN: 133324 Hom.: 1826 AF XY: 0.160 AC XY: 11653 AN XY: 72898

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.187 AC: 259787 AN: 1386364 Hom.: 25246 Cov.: 34 AF XY: 0.187 AC XY: 128005 AN XY: 684244

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.0809

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.174 AC: 26510 AN: 152304 Hom.: 2401 Cov.: 33 AF XY: 0.171 AC XY: 12772 AN XY: 74484

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.162

Alfa AF: 0.178 Hom.: 667

Bravo AF: 0.163

Asia WGS AF: 0.123 AC: 428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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.6G>A variant in the ETHE1 gene is reported as >16% in gnomAD, including >2,000 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) 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). -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2018	Variant summary: ETHE1 c.6G>A alters a non-conserved nucleotide resulting in a synonymous change. Four computational tools predict the variant has no significant impact on splicing while one predicts the variant strengthens a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.16 in 159212 control chromosomes in the gnomAD database, including 2280 homozygotes. The observed variant frequency is approximately 122-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ETHE1 causing Ethylmalonic Encephalopathy phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6G>A in individuals affected with Ethylmalonic Encephalopathy and no experimental evidence demonstrating its impact on protein function have been reported. A clinical diagnostic laboratory has a ClinVar submission after 2014 with a classification of "benign," along with another clinical diagnostic laboratory with no submission date as "benign." Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.1
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs3810381; hg19: chr19-44031324; COSMIC: COSV52676946;