Genetic Variant NM_014297.5:c.343G>C (chr19-43526233-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014297.5(ETHE1):c.343G>C(p.Glu115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E115K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ETHE1
NM_014297.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.795

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 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13051617).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
ETHE1	NM_014297.5	MANE Select	c.343G>C	p.Glu115Gln	missense	Exon 3 of 7	NP_055112.2
ETHE1	NM_001320867.2		c.310G>C	p.Glu104Gln	missense	Exon 3 of 7	NP_001307796.1	A0A0S2Z580
ETHE1	NM_001320869.2		c.81+864G>C		intron	N/A	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.343G>C	p.Glu115Gln	missense	Exon 3 of 7	ENSP00000292147.1	O95571
ETHE1	ENST00000600651.5	TSL:1	c.343G>C	p.Glu115Gln	missense	Exon 3 of 6	ENSP00000469037.1	M0QXB5
ZNF575	ENST00000458714.2	TSL:2	c.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000413956.2	B3KQ07

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ethylmalonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.032

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.099

MutationAssessor

Benign

1.4

PhyloP100

0.80

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.79

REVEL

Benign

0.22

Sift

Benign

0.32

Sift4G

Benign

0.51

Polyphen

0.0010

Vest4

0.069

MutPred

0.37

Loss of sheet (P = 0.0315)

MVP

0.86

MPC

0.55

ClinPred

0.16

GERP RS

3.3

Varity_R

0.45

gMVP

0.57

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over