rs182983506

Variant names:

• chr19-43526577-A-G
• rs182983506
• NM_014297.5:c.164T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014297.5(ETHE1):​c.164T>C​(p.Leu55Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. L55L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ETHE1 NM_014297.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.78
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	NM_014297.5	MANE Select	c.164T>C	p.Leu55Pro	missense	Exon 2 of 7	NP_055112.2
	ETHE1	NM_001320867.2		c.164T>C	p.Leu55Pro	missense	Exon 2 of 7	NP_001307796.1
	ETHE1	NM_001320868.2		c.-57T>C		5_prime_UTR	Exon 2 of 6	NP_001307797.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.164T>C	p.Leu55Pro	missense	Exon 2 of 7	ENSP00000292147.1
	ETHE1	ENST00000600651.5	TSL:1	c.164T>C	p.Leu55Pro	missense	Exon 2 of 6	ENSP00000469037.1
	ZNF575	ENST00000458714.2	TSL:2	c.86A>G	p.Gln29Arg	missense	Exon 2 of 5	ENSP00000413956.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Ethylmalonic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.81
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.67
MutPred		0.88		Gain of disorder (P = 0.0173)
MVP		0.96
MPC		1.9
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs182983506; hg19: chr19-44030729;