chr19-43525944-C-G

Position:

• chr19-43525944-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_014297.5(ETHE1):​c.375+257G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 566,054 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (15 hom.)
• Consequence: ETHE1 NM_014297.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.332

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 -16 ACMG points.

• BP6: Variant 19-43525944-C-G is Benign according to our data. Variant chr19-43525944-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1188087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1948/152272) while in subpopulation AFR AF= 0.044 (1827/41552). AF 95% confidence interval is 0.0423. There are 38 homozygotes in gnomad4. There are 885 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETHE1	NM_014297.5	c.375+257G>C		intron_variant		ENST00000292147.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETHE1	ENST00000292147.7	c.375+257G>C		intron_variant		1	NM_014297.5	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1947 AN: 152154 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00184 AC: 762 AN: 413782 Hom.: 15 Cov.: 4 AF XY: 0.00157 AC XY: 344 AN XY: 218624

Gnomad4 AFR exome AF: 0.0403

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000225

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000401

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.0128 AC: 1948 AN: 152272 Hom.: 38 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74452

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00908 Hom.: 1

Bravo AF: 0.0150

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.5
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs116311391; hg19: chr19-44030096;