chr18-57554416-T-C

Variant names:

• chr18-57554416-T-C
• rs536560
• NM_000140.5:c.921A>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.921A>G​(p.Pro307Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,613,744 control chromosomes in the GnomAD database, including 400,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43324 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357666 hom.)
• Consequence: FECH NM_000140.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.01
• Publications: 28 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 18-57554416-T-C is Benign according to our data. Variant chr18-57554416-T-C is described in ClinVar as Benign. ClinVar VariationId is 255312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 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.921A>G	p.Pro307Pro	synonymous	Exon 9 of 11	NP_000131.2	P22830-1
	FECH	NM_001012515.4		c.939A>G	p.Pro313Pro	synonymous	Exon 9 of 11	NP_001012533.1	P22830-2
	FECH	NM_001374778.1		c.921A>G	p.Pro307Pro	synonymous	Exon 9 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.921A>G	p.Pro307Pro	synonymous	Exon 9 of 11	ENSP00000262093.6	P22830-1
	FECH	ENST00000652755.1		c.939A>G	p.Pro313Pro	synonymous	Exon 9 of 11	ENSP00000498358.1	P22830-2
	FECH	ENST00000878110.1		c.921A>G	p.Pro307Pro	synonymous	Exon 9 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113061 AN: 152018 Hom.: 43283 Cov.: 32

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.717

GnomAD2 exomes AF: 0.692 AC: 174013 AN: 251442 AF XY: 0.693

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.624

Gnomad ASJ exome AF: 0.710

Gnomad EAS exome AF: 0.664

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.691

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.697 AC: 1019045 AN: 1461608 Hom.: 357666 Cov.: 56 AF XY: 0.698 AC XY: 507639 AN XY: 727110

African (AFR) AF: 0.938 AC: 31409 AN: 33476

American (AMR) AF: 0.633 AC: 28329 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 18597 AN: 26132

East Asian (EAS) AF: 0.679 AC: 26963 AN: 39700

South Asian (SAS) AF: 0.754 AC: 64991 AN: 86252

European-Finnish (FIN) AF: 0.559 AC: 29856 AN: 53410

Middle Eastern (MID) AF: 0.656 AC: 3784 AN: 5766

European-Non Finnish (NFE) AF: 0.695 AC: 772387 AN: 1111768

Other (OTH) AF: 0.708 AC: 42729 AN: 60384

GnomAD4 genome AF: 0.744 AC: 113163 AN: 152136 Hom.: 43324 Cov.: 32 AF XY: 0.739 AC XY: 54943 AN XY: 74344

African (AFR) AF: 0.927 AC: 38550 AN: 41564

American (AMR) AF: 0.687 AC: 10500 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2463 AN: 3470

East Asian (EAS) AF: 0.661 AC: 3412 AN: 5164

South Asian (SAS) AF: 0.751 AC: 3622 AN: 4824

European-Finnish (FIN) AF: 0.539 AC: 5687 AN: 10546

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

European-Non Finnish (NFE) AF: 0.688 AC: 46797 AN: 67970

Other (OTH) AF: 0.715 AC: 1507 AN: 2108

Alfa AF: 0.707 Hom.: 140687

Bravo AF: 0.758

Asia WGS AF: 0.704 AC: 2446 AN: 3476

EpiCase AF: 0.680

EpiControl AF: 0.685

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	0.19
DANN	Benign	0.40
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs536560; hg19: chr18-55221648; COSMIC: COSV50491796;