19-43526060-A-G

Variant names:

• chr19-43526060-A-G
• rs111747844
• NM_014297.5:c.375+141T>C

Variant summary

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

The NM_014297.5(ETHE1):​c.375+141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,309,620 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (69 hom.)
• Consequence: ETHE1 NM_014297.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.207
• 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]

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=-0.61).
• BP6: Variant 19-43526060-A-G is Benign according to our data. Variant chr19-43526060-A-G is described in ClinVar as Benign. ClinVar VariationId is 1226371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

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+141T>C		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.342+141T>C		intron	N/A	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.81+1037T>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+141T>C		intron	N/A	ENSP00000292147.1	O95571
	ETHE1	ENST00000600651.5	TSL:1	c.375+141T>C		intron	N/A	ENSP00000469037.1	M0QXB5
	ZNF575	ENST00000458714.2	TSL:2	c.-244A>G		5_prime_UTR	Exon 1 of 5	ENSP00000413956.2	B3KQ07

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2845 AN: 152080 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.00241 AC: 2786 AN: 1157422 Hom.: 69 Cov.: 15 AF XY: 0.00218 AC XY: 1272 AN XY: 584364

African (AFR) AF: 0.0646 AC: 1723 AN: 26658

American (AMR) AF: 0.00656 AC: 239 AN: 36446

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 13 AN: 22518

East Asian (EAS) AF: 0.00 AC: 0 AN: 36746

South Asian (SAS) AF: 0.000119 AC: 9 AN: 75858

European-Finnish (FIN) AF: 0.000388 AC: 16 AN: 41284

Middle Eastern (MID) AF: 0.0104 AC: 44 AN: 4244

European-Non Finnish (NFE) AF: 0.000498 AC: 430 AN: 863760

Other (OTH) AF: 0.00625 AC: 312 AN: 49908

GnomAD4 genome AF: 0.0187 AC: 2846 AN: 152198 Hom.: 72 Cov.: 32 AF XY: 0.0179 AC XY: 1335 AN XY: 74412

African (AFR) AF: 0.0624 AC: 2589 AN: 41506

American (AMR) AF: 0.0116 AC: 177 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68002

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00280 Hom.: 2

Bravo AF: 0.0218

Asia WGS AF: 0.00433 AC: 16 AN: 3478

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	-0.61
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		-0.21
Mutation Taster		=100/0	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: rs111747844; hg19: chr19-44030212;