chr18-57583662-T-C

Variant names:

• chr18-57583662-T-C
• rs492274
• NM_000140.5:c.67+2892A>G

Variant summary

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

The NM_000140.5(FECH):​c.67+2892A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,026 control chromosomes in the GnomAD database, including 15,744 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 0.45 (15744 hom., cov: 33)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.178
• Publications: 9 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=-0.61).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.641 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.67+2892A>G		intron	N/A	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.67+2892A>G		intron	N/A	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.67+2892A>G		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.67+2892A>G		intron	N/A	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.67+2892A>G		intron	N/A	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.67+2892A>G		intron	N/A	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67872 AN: 151908 Hom.: 15744 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.468

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

GnomAD4 genome AF: 0.447 AC: 67899 AN: 152026 Hom.: 15744 Cov.: 33 AF XY: 0.445 AC XY: 33048 AN XY: 74296

African (AFR) AF: 0.333 AC: 13790 AN: 41438

American (AMR) AF: 0.434 AC: 6629 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1608 AN: 3472

East Asian (EAS) AF: 0.659 AC: 3407 AN: 5170

South Asian (SAS) AF: 0.503 AC: 2424 AN: 4818

European-Finnish (FIN) AF: 0.422 AC: 4455 AN: 10548

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.499 AC: 33911 AN: 67978

Other (OTH) AF: 0.469 AC: 992 AN: 2114

Alfa AF: 0.482 Hom.: 27271

Bravo AF: 0.442

Asia WGS AF: 0.555 AC: 1929 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.18
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: rs492274; hg19: chr18-55250894;