rs3810381

Variant names:

• chr19-43527172-C-T
• rs3810381
• NM_014297.5:c.6G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BA1 BP7 BS2

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:10
• Conservation: PhyloP100: -1.84
• Publications: 14 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]

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ETHE1	NM_014297.5	c.6G>A	p.Ala2Ala	synonymous_variant	Exon 1 of 7	ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7	c.6G>A	p.Ala2Ala	synonymous_variant	Exon 1 of 7	1	NM_014297.5	ENSP00000292147.1

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

GnomAD2 exomes AF: 0.157 AC: 20954 AN: 133324 AF XY: 0.160

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 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

African (AFR) AF: 0.169 AC: 5323 AN: 31566

American (AMR) AF: 0.0809 AC: 2898 AN: 35832

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3783 AN: 25128

East Asian (EAS) AF: 0.148 AC: 5307 AN: 35760

South Asian (SAS) AF: 0.152 AC: 12018 AN: 79256

European-Finnish (FIN) AF: 0.216 AC: 8032 AN: 37202

Middle Eastern (MID) AF: 0.120 AC: 596 AN: 4986

European-Non Finnish (NFE) AF: 0.196 AC: 211868 AN: 1078828

Other (OTH) AF: 0.172 AC: 9962 AN: 57806

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

African (AFR) AF: 0.170 AC: 7077 AN: 41566

American (AMR) AF: 0.110 AC: 1688 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.136 AC: 703 AN: 5174

South Asian (SAS) AF: 0.147 AC: 711 AN: 4830

European-Finnish (FIN) AF: 0.213 AC: 2256 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13068 AN: 68024

Other (OTH) AF: 0.162 AC: 343 AN: 2114

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:10

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Benign:5

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2021

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

not provided Benign:3

Feb 15, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.1
DANN	Benign	0.93
PhyloP100		-1.8
PromoterAI		-0.58	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	polymorphism (auto)

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