chr19-43527172-C-T

Position:

chr19-43527172-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP7BS2BA1

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

Scores

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: -1.84

Variant links:

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 links:

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]

ZNF575 links:

ETHE1 (HGNC:):

ETHE1 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.6G>A	p.Ala2Ala	synonymous_variant	1/7	ENST00000292147.7	NP_055112.2	O95571A0A0S2Z5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7 linkuse as main transcript	c.6G>A	p.Ala2Ala	synonymous_variant	1/7	1	NM_014297.5	ENSP00000292147.1		O95571

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26481

AN:

152186

Hom.:

2401

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.187

AC XY:

128005

AN XY:

684244

show subpopulations

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.:

AF XY:

0.171

AC XY:

12772

AN XY:

74484

show subpopulations

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:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ethylmalonic encephalopathy

Benign:5

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over