chr19-43526151-T-G

Variant names:

• chr19-43526151-T-G
• rs142759186
• NM_014297.5:c.375+50A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.75
• Publications: 1 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 -20 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 VariationId is 1192898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.375+50A>C		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.342+50A>C		intron	N/A	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.81+946A>C		intron	N/A	NP_001307798.1	A0A0S2Z5N8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.375+50A>C		intron	N/A	ENSP00000292147.1	O95571
	ETHE1	ENST00000600651.5	TSL:1	c.375+50A>C		intron	N/A	ENSP00000469037.1	M0QXB5
	ZNF575	ENST00000458714.2	TSL:2	c.-153T>G		5_prime_UTR	Exon 1 of 5	ENSP00000413956.2	B3KQ07

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

GnomAD2 exomes AF: 0.00504 AC: 1260 AN: 250246 AF XY: 0.00507

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 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

African (AFR) AF: 0.00108 AC: 36 AN: 33468

American (AMR) AF: 0.00418 AC: 187 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00417 AC: 360 AN: 86238

European-Finnish (FIN) AF: 0.000901 AC: 48 AN: 53260

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00971 AC: 10791 AN: 1111798

Other (OTH) AF: 0.00583 AC: 352 AN: 60364

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

African (AFR) AF: 0.00181 AC: 75 AN: 41452

American (AMR) AF: 0.00583 AC: 89 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10572

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00836 AC: 568 AN: 67968

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00704 Hom.: 3

Bravo AF: 0.00512

ClinVar

ClinVar submissions

Significance: Likely 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	-0.82
CADD	Benign	2.4
DANN	Benign	0.76
PhyloP100		-2.8
Mutation Taster		=300/0	polymorphism

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: rs142759186; hg19: chr19-44030303;