NM_014297.5:c.375+257G>C

Variant names:

• chr19-43525944-C-G
• rs116311391
• NM_014297.5:c.375+257G>C

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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+257G>C		intron	N/A	NP_055112.2
	ETHE1	NM_001320867.2		c.342+257G>C		intron	N/A	NP_001307796.1	A0A0S2Z580
	ETHE1	NM_001320869.2		c.81+1153G>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+257G>C		intron	N/A	ENSP00000292147.1	O95571
	ETHE1	ENST00000600651.5	TSL:1	c.375+257G>C		intron	N/A	ENSP00000469037.1	M0QXB5
	ZNF575	ENST00000458714.2	TSL:2	c.-360C>G		5_prime_UTR	Exon 1 of 5	ENSP00000413956.2	B3KQ07

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

African (AFR) AF: 0.0403 AC: 476 AN: 11804

American (AMR) AF: 0.00465 AC: 81 AN: 17408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12604

East Asian (EAS) AF: 0.00 AC: 0 AN: 27256

South Asian (SAS) AF: 0.0000225 AC: 1 AN: 44522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24900

Middle Eastern (MID) AF: 0.00492 AC: 9 AN: 1830

European-Non Finnish (NFE) AF: 0.000401 AC: 100 AN: 249578

Other (OTH) AF: 0.00398 AC: 95 AN: 23880

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

African (AFR) AF: 0.0440 AC: 1827 AN: 41552

American (AMR) AF: 0.00458 AC: 70 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68022

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00908 Hom.: 1

Bravo AF: 0.0150

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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	-0.67
CADD	Benign	9.5
DANN	Benign	0.84
PhyloP100		0.33
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116311391; hg19: chr19-44030096;