19-43507745-C-T

Variant names:

• chr19-43507745-C-T
• rs2599450
• ENST00000600651.5:c.*128G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000600651.5(ETHE1):​c.*128G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (5861 hom., cov: 9)
  • Exomes 𝑓: 0.36 (24629 hom.)
• Consequence: ETHE1 ENST00000600651.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.402
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-43507745-C-T is Benign according to our data. Variant chr19-43507745-C-T is described in ClinVar as Benign. ClinVar VariationId is 1260599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

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+199G>A		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.679+199G>A		intron	N/A	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.418+199G>A		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.*128G>A		3_prime_UTR	Exon 6 of 6	ENSP00000469037.1	M0QXB5
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.712+199G>A		intron	N/A	ENSP00000292147.1	O95571
	ETHE1	ENST00000880125.1		c.877+199G>A		intron	N/A	ENSP00000550184.1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 22053 AN: 68430 Hom.: 5853 Cov.: 9

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.319

GnomAD4 exome AF: 0.357 AC: 85308 AN: 239186 Hom.: 24629 Cov.: 2 AF XY: 0.371 AC XY: 48216 AN XY: 130082

African (AFR) AF: 0.348 AC: 2299 AN: 6608

American (AMR) AF: 0.528 AC: 6015 AN: 11394

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 1652 AN: 6442

East Asian (EAS) AF: 0.433 AC: 4961 AN: 11458

South Asian (SAS) AF: 0.554 AC: 20514 AN: 37022

European-Finnish (FIN) AF: 0.277 AC: 3419 AN: 12364

Middle Eastern (MID) AF: 0.335 AC: 283 AN: 844

European-Non Finnish (NFE) AF: 0.300 AC: 42268 AN: 141044

Other (OTH) AF: 0.324 AC: 3897 AN: 12010

GnomAD4 genome AF: 0.322 AC: 22073 AN: 68506 Hom.: 5861 Cov.: 9 AF XY: 0.323 AC XY: 10493 AN XY: 32502

African (AFR) AF: 0.289 AC: 4680 AN: 16170

American (AMR) AF: 0.346 AC: 2006 AN: 5794

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 633 AN: 1974

East Asian (EAS) AF: 0.470 AC: 973 AN: 2072

South Asian (SAS) AF: 0.337 AC: 508 AN: 1508

European-Finnish (FIN) AF: 0.247 AC: 923 AN: 3742

Middle Eastern (MID) AF: 0.245 AC: 24 AN: 98

European-Non Finnish (NFE) AF: 0.332 AC: 11938 AN: 35912

Other (OTH) AF: 0.318 AC: 287 AN: 902

Alfa AF: 0.421 Hom.: 742

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.3
DANN	Benign	0.74
PhyloP100		-0.40
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: rs2599450; hg19: chr19-44011897;