19-43526358-G-C

Variant names:

• chr19-43526358-G-C
• rs199921503
• NM_014297.5:c.227-9C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.227-9C>G (NM_014297.5) variant in ETHE1 is an intronic variant which is located in intron 2 (intron 2/6). The highest population minor allele frequency for the c.227-9C>G in gnomAD v2.1.1 is 0.00321 (905/282370 alleles, no homozygotes) in the general population, which is higher than the ClinGen ETHE1 threshold >0.001 for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign, and therefore not causative of Autosomal Recessive Ethylmalonic Encephalopathy. ACMG/AMP criteria applied, as specified by the ClinGen ETHE1 VCEP (version 1.0): BA1. Approved 7/6/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290777/MONDO:0011229/014

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: ETHE1 NM_014297.5 intron
• Scores: Splicing: ADA: 0.009077
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.0430
• Publications: 2 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]

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

Our verdict: Benign. The variant received -8 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.227-9C>G		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.227-42C>G		intron	N/A	NP_001307796.1
	ETHE1	NM_001320869.2		c.81+739C>G		intron	N/A	NP_001307798.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.227-9C>G		intron	N/A	ENSP00000292147.1
	ETHE1	ENST00000600651.5	TSL:1	c.227-9C>G		intron	N/A	ENSP00000469037.1
	ZNF575	ENST00000880320.1		c.-431G>C		5_prime_UTR	Exon 1 of 4	ENSP00000550379.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00315 AC: 790 AN: 251004 AF XY: 0.00338

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00755

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00349 AC: 5107 AN: 1461830 Hom.: 15 Cov.: 31 AF XY: 0.00351 AC XY: 2553 AN XY: 727222

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00270 AC: 233 AN: 86254

European-Finnish (FIN) AF: 0.00858 AC: 458 AN: 53410

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00368 AC: 4094 AN: 1111978

Other (OTH) AF: 0.00359 AC: 217 AN: 60386

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74478

African (AFR) AF: 0.000626 AC: 26 AN: 41564

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00403 AC: 274 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00260 Hom.: 1

Bravo AF: 0.00223

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Ethylmalonic encephalopathy (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		0.043
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0091
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.11		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: rs199921503; hg19: chr19-44030510;