rs1366031091

Variant names:

• chr19-43506854-G-A
• rs1366031091
• NM_014297.5:c.761C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-43506854-G-A
• chr19-43506854-G-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: This variant was classified as a variant of uncertain significance as there has not been sufficient evidence to support either a benign or a pathogenic classification. Specifically, this variant has not been reported in the literature in affected or unaffected patients, has no published functional data, and is not present in population databases to assess allele frequency. LINK:https://erepo.genome.network/evrepo/ui/classification/CA406174565/MONDO:0011229/014

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ETHE1 NM_014297.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 0.773
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.761C>T	p.Ala254Val	missense	Exon 7 of 7	NP_055112.2
	ETHE1	NM_001320867.2		c.728C>T	p.Ala243Val	missense	Exon 7 of 7	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.467C>T	p.Ala156Val	missense	Exon 5 of 5	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.761C>T	p.Ala254Val	missense	Exon 7 of 7	ENSP00000292147.1	O95571
	ETHE1	ENST00000880125.1		c.926C>T	p.Ala309Val	missense	Exon 8 of 8	ENSP00000550184.1
	ETHE1	ENST00000970449.1		c.854C>T	p.Ala285Val	missense	Exon 8 of 8	ENSP00000640508.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461308 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111836

Other (OTH) AF: 0.0000331 AC: 2 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Ethylmalonic encephalopathy (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.77
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.26
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.010	B
Vest4		0.13
MutPred		0.30		Gain of catalytic residue at A254 (P = 0.1163)
MVP		0.79
MPC		0.65
ClinPred		0.36	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.46
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1366031091; hg19: chr19-44011006;