rs116440799

Positions:

• chr19-43527117-C-A
• chr19-43527117-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

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 ENST00000292147.7 missense
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.802

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]

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ETHE1	NM_014297.5	c.61G>T	p.Ala21Ser	missense_variant	1/7	ENST00000292147.7	NP_055112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ETHE1	ENST00000292147.7	c.61G>T	p.Ala21Ser	missense_variant	1/7	1	NM_014297.5	ENSP00000292147	P1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2815 AN: 152234 Hom.: 70 Cov.: 32

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

GnomAD3 exomes AF: 0.00478 AC: 741 AN: 155116 Hom.: 20 AF XY: 0.00394 AC XY: 336 AN XY: 85178

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 SAS exome AF: 0.0000835

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.: 79 Cov.: 32 AF XY: 0.00213 AC XY: 1478 AN XY: 694728

Gnomad4 AFR exome AF: 0.0640

Gnomad4 AMR exome AF: 0.00637

Gnomad4 ASJ exome AF: 0.000593

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000124

Gnomad4 FIN exome AF: 0.000288

Gnomad4 NFE exome AF: 0.000479

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.0185 AC: 2816 AN: 152350 Hom.: 70 Cov.: 32 AF XY: 0.0177 AC XY: 1322 AN XY: 74498

Gnomad4 AFR AF: 0.0617

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00522 Hom.: 5

Bravo AF: 0.0216

ESP6500AA AF: 0.0346 AC: 132

ESP6500EA AF: 0.00116 AC: 9

ExAC AF: 0.00425 AC: 482

Asia WGS AF: 0.00375 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Ethylmalonic encephalopathy Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	May 06, 2021	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). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 28, 2019	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 21, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2014

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	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.69	N;N
PrimateAI	Uncertain	0.61	T
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	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs116440799; hg19: chr19-44031269;