rs2269222

Variant names:

• chr18-57566146-C-T
• rs2269222
• NM_000140.5:c.598+301G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000140.5(FECH):​c.598+301G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 152,130 control chromosomes in the GnomAD database, including 783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.090 (783 hom., cov: 32)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.641
• Publications: 3 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: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal erythropoietic protoporphyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 18-57566146-C-T is Benign according to our data. Variant chr18-57566146-C-T is described in ClinVar as Benign. ClinVar VariationId is 1282607.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.598+301G>A		intron_variant	Intron 5 of 10	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.598+301G>A		intron_variant	Intron 5 of 10	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13642 AN: 152012 Hom.: 783 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0846

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

GnomAD4 genome AF: 0.0898 AC: 13656 AN: 152130 Hom.: 783 Cov.: 32 AF XY: 0.0898 AC XY: 6676 AN XY: 74376

African (AFR) AF: 0.156 AC: 6478 AN: 41498

American (AMR) AF: 0.0548 AC: 838 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3472

East Asian (EAS) AF: 0.149 AC: 769 AN: 5174

South Asian (SAS) AF: 0.114 AC: 550 AN: 4810

European-Finnish (FIN) AF: 0.0662 AC: 701 AN: 10586

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0562 AC: 3824 AN: 67984

Other (OTH) AF: 0.0861 AC: 182 AN: 2114

Alfa AF: 0.0649 Hom.: 656

Bravo AF: 0.0895

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.41
PhyloP100		-0.64
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: rs2269222; hg19: chr18-55233378;