Genetic Variant ETHE1:c.*55G>T (chr19-43506795-C-A) – ACMG Classification: Benign (-12 pts)

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 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

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:2

Conservation

PhyloP100: 0.994

Publications

0 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 Gene-Disease associations (from GenCC):

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

ETHE1 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014297.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ETHE1	NM_014297.5	MANE Select	c.*55G>T	3_prime_UTR	Exon 7 of 7	NP_055112.2
ETHE1	NM_001320867.2		c.*55G>T	3_prime_UTR	Exon 7 of 7	NP_001307796.1	A0A0S2Z580
ETHE1	NM_001320869.2		c.*55G>T	3_prime_UTR	Exon 5 of 5	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.*55G>T	3_prime_UTR	Exon 7 of 7	ENSP00000292147.1	O95571
ETHE1	ENST00000880125.1		c.*55G>T	3_prime_UTR	Exon 8 of 8	ENSP00000550184.1
ETHE1	ENST00000970449.1		c.*55G>T	3_prime_UTR	Exon 8 of 8	ENSP00000640508.1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

226

AN:

152110

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00251

AC XY:

1738

AN XY:

692622

show subpopulations

African (AFR)

AF:

0.000377

AC:

AN:

31860

American (AMR)

AF:

0.000740

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

25644

East Asian (EAS)

AF:

0.00

AC:

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:

AN:

4450

European-Non Finnish (NFE)

AF:

0.00190

AC:

1982

AN:

1042944

Other (OTH)

AF:

0.00258

AC:

149

AN:

57756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

158

316

475

633

791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00148

AC:

226

AN:

152228

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41542

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00191

AC:

130

AN:

68014

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000318

Hom.:

Bravo

AF:

0.00134

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ethylmalonic encephalopathy (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.3

(source)

DANN

Benign

0.48

PhyloP100

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over