19-43507763-T-C

Variant names:

• chr19-43507763-T-C
• rs12985024
• ENST00000600651.5:c.*110A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BA1 BP7 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.712+181A>G variant in the ETHE1 gene is reported as >12% in gnomAD, including 167 homozygotes, which is high enough 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 silico splicing predictors (Splice AI) for this intronic variant do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA308740635/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.14 (903 hom., cov: 7)
  • Exomes 𝑓: 0.15 (4383 hom.)
• Consequence: ETHE1 ENST00000600651.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.118
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000600651.5. 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.712+181A>G		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.679+181A>G		intron	N/A	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.418+181A>G		intron	N/A	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000600651.5	TSL:1	c.*110A>G		3_prime_UTR	Exon 6 of 6	ENSP00000469037.1	M0QXB5
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.712+181A>G		intron	N/A	ENSP00000292147.1	O95571
	ETHE1	ENST00000880125.1		c.877+181A>G		intron	N/A	ENSP00000550184.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 7279 AN: 51350 Hom.: 902 Cov.: 7

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0709

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.145 AC: 36073 AN: 248696 Hom.: 4383 Cov.: 4 AF XY: 0.142 AC XY: 19318 AN XY: 136020

African (AFR) AF: 0.154 AC: 1013 AN: 6580

American (AMR) AF: 0.0580 AC: 871 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 826 AN: 6594

East Asian (EAS) AF: 0.121 AC: 1721 AN: 14282

South Asian (SAS) AF: 0.106 AC: 4241 AN: 40076

European-Finnish (FIN) AF: 0.202 AC: 2364 AN: 11706

Middle Eastern (MID) AF: 0.105 AC: 92 AN: 876

European-Non Finnish (NFE) AF: 0.164 AC: 23167 AN: 141558

Other (OTH) AF: 0.148 AC: 1778 AN: 12014

GnomAD4 genome AF: 0.142 AC: 7281 AN: 51366 Hom.: 903 Cov.: 7 AF XY: 0.142 AC XY: 3406 AN XY: 23998

African (AFR) AF: 0.122 AC: 1448 AN: 11856

American (AMR) AF: 0.0949 AC: 381 AN: 4016

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 201 AN: 1612

East Asian (EAS) AF: 0.0962 AC: 169 AN: 1756

South Asian (SAS) AF: 0.101 AC: 112 AN: 1112

European-Finnish (FIN) AF: 0.225 AC: 423 AN: 1884

Middle Eastern (MID) AF: 0.183 AC: 11 AN: 60

European-Non Finnish (NFE) AF: 0.158 AC: 4433 AN: 28124

Other (OTH) AF: 0.126 AC: 82 AN: 650

Alfa AF: 0.275 Hom.: 185

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ethylmalonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.80
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12985024; hg19: chr19-44011915;