rs2269219

chr18-57580222-G-Achr18-57580222-G-Cchr18-57580222-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000140.5(FECH):c.68-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,044 control chromosomes in the GnomAD database, including 38,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (6866 hom., cov: 32)
  • Exomes 𝑓: 0.19 (31549 hom.)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• Conservation: PhyloP100: 0.509

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-57580222-G-A is Benign according to our data. Variant chr18-57580222-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}. Variant chr18-57580222-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FECH	NM_000140.5	c.68-23C>T		intron_variant		ENST00000262093.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FECH	ENST00000262093.11	c.68-23C>T		intron_variant		1	NM_000140.5

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41599 AN: 151926 Hom.: 6851 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.251 AC: 62889 AN: 250832 Hom.: 9458 AF XY: 0.240 AC XY: 32569 AN XY: 135626

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.311

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.194 AC: 283768 AN: 1461000 Hom.: 31549 Cov.: 34 AF XY: 0.194 AC XY: 141175 AN XY: 726836

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.366

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.274 AC: 41673 AN: 152044 Hom.: 6866 Cov.: 32 AF XY: 0.278 AC XY: 20647 AN XY: 74320

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.262

Alfa AF: 0.189 Hom.: 4713

Bravo AF: 0.288

Asia WGS AF: 0.294 AC: 1020 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Protoporphyria, erythropoietic, 1 Pathogenic:1 Uncertain:1 Benign:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Dec 08, 2021	ACMG categories: PS5,BS2,BP6,BP7 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 8280787, 1729699, 27884173, 26789144) -

Jaundice;C0041834:Erythema Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.0
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2269219; hg19: chr18-55247454; COSMIC: COSV50490971;