18-57569195-C-T

Variant names:

• chr18-57569195-C-T
• rs1788002
• NM_000140.5:c.463+2197G>A

Variant summary

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

The NM_000140.5(FECH):​c.463+2197G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 152,166 control chromosomes in the GnomAD database, including 14,527 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 0.42 (14527 hom., cov: 34)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000140.5. 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
	FECH	NM_000140.5	MANE Select	c.463+2197G>A		intron	N/A	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.481+2197G>A		intron	N/A	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.463+2197G>A		intron	N/A	NP_001361707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.463+2197G>A		intron	N/A	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.481+2197G>A		intron	N/A	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.463+2197G>A		intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64461 AN: 152048 Hom.: 14524 Cov.: 34

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.424 AC: 64495 AN: 152166 Hom.: 14527 Cov.: 34 AF XY: 0.429 AC XY: 31909 AN XY: 74388

African (AFR) AF: 0.271 AC: 11267 AN: 41522

American (AMR) AF: 0.529 AC: 8089 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1838 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3024 AN: 5180

South Asian (SAS) AF: 0.602 AC: 2907 AN: 4828

European-Finnish (FIN) AF: 0.440 AC: 4657 AN: 10574

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31339 AN: 67986

Other (OTH) AF: 0.441 AC: 931 AN: 2110

Alfa AF: 0.449 Hom.: 23921

Bravo AF: 0.420

Asia WGS AF: 0.569 AC: 1977 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	4.9
DANN	Benign	0.39
PhyloP100		0.14
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: rs1788002; hg19: chr18-55236427;