19-43527099-G-T

Position:

• chr19-43527099-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_014297.5(ETHE1):​c.79C>A​(p.Gln27Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000285 in 1,402,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ETHE1 NM_014297.5 missense, splice_region
• Scores: Splicing: ADA: 0.3269
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.00

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]

ETHE1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-43527099-G-T is Pathogenic according to our data. Variant chr19-43527099-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 617791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ETHE1	NM_014297.5	c.79C>A	p.Gln27Lys	missense_variant, splice_region_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.79C>A	p.Gln27Lys	missense_variant, splice_region_variant	1/7	1	NM_014297.5	ENSP00000292147.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000645 AC: 1 AN: 154964 Hom.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 84918

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1402940 Hom.: 0 Cov.: 32 AF XY: 0.00000577 AC XY: 4 AN XY: 693708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000870 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ethylmalonic encephalopathy Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Core Molecular Diagnostic Lab, McGill University Health Centre	Feb 12, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 22, 2024	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ETHE1: PM3:Strong, PM2, PP3, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2017	Not observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 30349987, 19289697) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.48
MutPred		0.55		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.97
MPC		1.4
ClinPred		0.97	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.65
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

LitVar

Other links and lift over

dbSNP: rs749803238; hg19: chr19-44031251;