19-43526151-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014297.5(ETHE1):c.375+50A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00783 in 1,613,460 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (56 hom.)
• Consequence: ETHE1 NM_014297.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.75

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-43526151-T-G is Benign according to our data. Variant chr19-43526151-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1192898.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00525 (798/152020) while in subpopulation NFE AF= 0.00836 (568/67968). AF 95% confidence interval is 0.00779. There are 2 homozygotes in gnomad4. There are 384 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETHE1	NM_014297.5	c.375+50A>C		intron_variant		ENST00000292147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETHE1	ENST00000292147.7	c.375+50A>C		intron_variant		1	NM_014297.5	P1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 798 AN: 151902 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00836

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00504 AC: 1260 AN: 250246 Hom.: 3 AF XY: 0.00507 AC XY: 686 AN XY: 135412

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.000605

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00809 AC: 11828 AN: 1461440 Hom.: 56 Cov.: 31 AF XY: 0.00795 AC XY: 5781 AN XY: 726984

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.000901

Gnomad4 NFE exome AF: 0.00971

Gnomad4 OTH exome AF: 0.00583

GnomAD4 genome AF: 0.00525 AC: 798 AN: 152020 Hom.: 2 Cov.: 32 AF XY: 0.00517 AC XY: 384 AN XY: 74326

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00583

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00836

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00669 Hom.: 2

Bravo AF: 0.00512

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.4
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs142759186; hg19: chr19-44030303;