rs119103249

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_014297.5(ETHE1):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

ETHE1
NM_014297.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.50

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 28 codons. Genomic position: 43526659. Lost 0.107 part of the original CDS.

PS1

Another start lost variant in NM_014297.5 (ETHE1) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-43527175-C-A is Pathogenic according to our data. Variant chr19-43527175-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ETHE1	NM_014297.5 link	c.3G>T	p.Met1?	start_lost	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.3G>T	p.Met1?	start_lost	Exon 1 of 7	1	NM_014297.5	ENSP00000292147.1		O95571

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000754

AC:

AN:

132620

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1385658

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31548

American (AMR)

AF:

0.00

AC:

AN:

35778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25124

East Asian (EAS)

AF:

0.00

AC:

AN:

35750

South Asian (SAS)

AF:

0.00

AC:

AN:

79222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4916

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078598

Other (OTH)

AF:

0.0000173

AC:

AN:

57774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000106

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ethylmalonic encephalopathy

Pathogenic:3Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 02, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jan 03, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Met1? (ATG>ATT): c.3 G>T in exon 1 of the ETHE1 gene (NM_014297.3). The c.3 G>T mutation in the ETHE1 gene has been reported previously in association with ethylmalonic encephalopathy (Tiranti et al., 2004). The mutation alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. This result is expected consistent with a diagnosis of ethylmalonic encephalopathy. The variant is found in MITONUC-MITOP panel(s)." -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.033

PhyloP100

1.5

PROVEAN

Benign

-0.13

N;.

REVEL

Uncertain

0.56

Sift

Benign

0.034

D;.

Sift4G

Benign

0.12

T;T

Polyphen

0.0020

B;.

Vest4

0.86

MutPred

0.99

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);

MVP

0.93

ClinPred

0.93

GERP RS

3.0

PromoterAI

-0.74

Under-expression

(source)

Varity_R

0.37

gMVP

0.80

Mutation Taster

=4/196

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over