18-57559151-G-C

Variant names:

• chr18-57559151-G-C
• rs536765
• NM_000140.5:c.798C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000140.5(FECH):​c.798C>G​(p.Pro266Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,601,626 control chromosomes in the GnomAD database, including 393,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P266P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42982 hom., cov: 31)
  • Exomes 𝑓: 0.69 (350841 hom.)
• Consequence: FECH NM_000140.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.75
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 18-57559151-G-C is Benign according to our data. Variant chr18-57559151-G-C is described in ClinVar as Benign. ClinVar VariationId is 255311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 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.798C>G	p.Pro266Pro	synonymous	Exon 7 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.816C>G	p.Pro272Pro	synonymous	Exon 7 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.798C>G	p.Pro266Pro	synonymous	Exon 7 of 10	NP_001361707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.798C>G	p.Pro266Pro	synonymous	Exon 7 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.816C>G	p.Pro272Pro	synonymous	Exon 7 of 11	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.798C>G	p.Pro266Pro	synonymous	Exon 7 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112491 AN: 151894 Hom.: 42944 Cov.: 31

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.687 AC: 172526 AN: 251246 AF XY: 0.687

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.693 AC: 1004448 AN: 1449614 Hom.: 350841 Cov.: 28 AF XY: 0.694 AC XY: 500694 AN XY: 721894

African (AFR) AF: 0.942 AC: 31271 AN: 33208

American (AMR) AF: 0.632 AC: 28233 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18337 AN: 26038

East Asian (EAS) AF: 0.646 AC: 25575 AN: 39598

South Asian (SAS) AF: 0.740 AC: 63658 AN: 86024

European-Finnish (FIN) AF: 0.556 AC: 29625 AN: 53282

Middle Eastern (MID) AF: 0.655 AC: 3768 AN: 5750

European-Non Finnish (NFE) AF: 0.692 AC: 761854 AN: 1101072

Other (OTH) AF: 0.703 AC: 42127 AN: 59948

GnomAD4 genome AF: 0.741 AC: 112590 AN: 152012 Hom.: 42982 Cov.: 31 AF XY: 0.735 AC XY: 54630 AN XY: 74280

African (AFR) AF: 0.929 AC: 38548 AN: 41504

American (AMR) AF: 0.683 AC: 10430 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2433 AN: 3470

East Asian (EAS) AF: 0.636 AC: 3268 AN: 5140

South Asian (SAS) AF: 0.736 AC: 3546 AN: 4820

European-Finnish (FIN) AF: 0.539 AC: 5676 AN: 10536

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.686 AC: 46585 AN: 67954

Other (OTH) AF: 0.710 AC: 1500 AN: 2114

Alfa AF: 0.671 Hom.: 8843

Bravo AF: 0.754

EpiCase AF: 0.676

EpiControl AF: 0.682

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Protoporphyria, erythropoietic, 1 (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.41
PhyloP100		-2.7
PromoterAI		0.055	Neutral
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: rs536765; hg19: chr18-55226383; COSMIC: COSV50490970;