rs116440799

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.61G>T variant in the ETHE1 gene is 0.7% in gnomAD, including 33 homozygotes which is a high enough frequency 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 summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1 specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the ETHE1 expert panel on 2/23/2021 and approved on 2/23/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290780/MONDO:0011229/014

Frequency

Genomes: 𝑓 0.018 ( 70 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 79 hom. )

Consequence

ETHE1
NM_014297.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.802

Publications

5 publications found

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:

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ACMG classification

Classification was made for transcript

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 link	c.61G>T	p.Ala21Ser	missense_variant	Exon 1 of 7	ENST00000292147.7	NP_055112.2	O95571A0A0S2Z5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7 link	c.61G>T	p.Ala21Ser	missense_variant	Exon 1 of 7	1	NM_014297.5	ENSP00000292147.1		O95571

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2815

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00478

AC:

741

AN:

155116

AF XY:

0.00394

show subpopulations

Gnomad AFR exome

AF:

0.0638

Gnomad AMR exome

AF:

0.00540

Gnomad ASJ exome

AF:

0.000833

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000965

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00233

AC:

3272

AN:

1404570

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1478

AN XY:

694728

show subpopulations

African (AFR)

AF:

0.0640

AC:

2052

AN:

32066

American (AMR)

AF:

0.00637

AC:

244

AN:

38276

Ashkenazi Jewish (ASJ)

AF:

0.000593

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

36552

South Asian (SAS)

AF:

0.000124

AC:

AN:

80586

European-Finnish (FIN)

AF:

0.000288

AC:

AN:

41630

Middle Eastern (MID)

AF:

0.0124

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.000479

AC:

520

AN:

1086128

Other (OTH)

AF:

0.00598

AC:

349

AN:

58374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

184

368

551

735

919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0185

AC:

2816

AN:

152350

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1322

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0617

AC:

2564

AN:

41582

American (AMR)

AF:

0.0114

AC:

175

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68026

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00661

Hom.:

Bravo

AF:

0.0216

ESP6500AA

AF:

0.0346

AC:

132

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00425

AC:

482

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ethylmalonic encephalopathy

Benign:5

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

May 06, 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.61G>T variant in the ETHE1 gene is 0.7% in gnomAD, including 33 homozygotes which is a high enough frequency 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 summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1 specific ACMG/AMP criteria applied: (BA1, BS2). -

not provided

Benign:3

Mar 16, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 21, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 17, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.34

N;.

PhyloP100

0.80

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.74

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

0.88

T;T

Polyphen

0.0

B;.

Vest4

0.29

MVP

0.80

MPC

0.51

ClinPred

0.0018

GERP RS

3.0

PromoterAI

0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.47

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over