19-43527144-G-T

Variant names:

• chr19-43527144-G-T
• rs1555765701
• NM_014297.5:c.34C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014297.5(ETHE1):​c.34C>A​(p.Gln12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ETHE1 NM_014297.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22978437).

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.34C>A	p.Gln12Lys	missense	Exon 1 of 7	NP_055112.2
	ETHE1	NM_001320867.2		c.34C>A	p.Gln12Lys	missense	Exon 1 of 7	NP_001307796.1
	ETHE1	NM_001320869.2		c.34C>A	p.Gln12Lys	missense	Exon 1 of 5	NP_001307798.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETHE1	ENST00000292147.7	TSL:1 MANE Select	c.34C>A	p.Gln12Lys	missense	Exon 1 of 7	ENSP00000292147.1
	ETHE1	ENST00000600651.5	TSL:1	c.34C>A	p.Gln12Lys	missense	Exon 1 of 6	ENSP00000469037.1
	ETHE1	ENST00000594342.5	TSL:2	n.34C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000469652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396248 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689910

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31898

American (AMR) AF: 0.00 AC: 0 AN: 37026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 36190

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082854

Other (OTH) AF: 0.00 AC: 0 AN: 58142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.31
Sift	Benign	0.29	T
Sift4G	Benign	0.32	T
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.49		Loss of helix (P = 3e-04)
MVP		0.85
MPC		0.71
ClinPred		0.13	T
GERP RS		3.0
PromoterAI		0.27	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.15
gMVP		0.84
Mutation Taster		=97/3	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: rs1555765701; hg19: chr19-44031296; COSMIC: COSV52678502;