18-57568045-T-C

Variant names:

• chr18-57568045-T-C
• rs1790619
• NM_000140.5:c.464-1464A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001012515.4(FECH):​c.482-1464A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 152,112 control chromosomes in the GnomAD database, including 31,736 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (31736 hom., cov: 33)
• Consequence: FECH NM_001012515.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.192
• Publications: 6 publications found

Genes affected

FECH (HGNC:3647): (ferrochelatase) The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.[provided by RefSeq, May 2010]

FECH Gene-Disease associations (from GenCC):

• protoporphyria, erythropoietic, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012515.4. 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
	FECH	NM_000140.5	MANE Select	c.464-1464A>G		intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.482-1464A>G		intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.464-1464A>G		intron	N/A	NP_001361707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.464-1464A>G		intron	N/A	ENSP00000262093.6
	FECH	ENST00000652755.1		c.482-1464A>G		intron	N/A	ENSP00000498358.1
	FECH	ENST00000878110.1		c.464-1464A>G		intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97801 AN: 151994 Hom.: 31713 Cov.: 33

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.629

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.644 AC: 97890 AN: 152112 Hom.: 31736 Cov.: 33 AF XY: 0.640 AC XY: 47546 AN XY: 74342

African (AFR) AF: 0.684 AC: 28373 AN: 41482

American (AMR) AF: 0.664 AC: 10151 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2265 AN: 3472

East Asian (EAS) AF: 0.618 AC: 3195 AN: 5174

South Asian (SAS) AF: 0.673 AC: 3248 AN: 4824

European-Finnish (FIN) AF: 0.499 AC: 5277 AN: 10568

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43436 AN: 67984

Other (OTH) AF: 0.628 AC: 1325 AN: 2110

Alfa AF: 0.591 Hom.: 3793

Bravo AF: 0.654

Asia WGS AF: 0.648 AC: 2252 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.45
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs1790619; hg19: chr18-55235277;