rs2269221

Variant names:

• chr18-57568208-G-A
• rs2269221
• NM_000140.5:c.464-1627C>T

Variant summary

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

The NM_000140.5(FECH):​c.464-1627C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,138 control chromosomes in the GnomAD database, including 1,326 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 0.11 (1326 hom., cov: 33)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.145
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	NM_000140.5	MANE Select	c.464-1627C>T		intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.482-1627C>T		intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.464-1627C>T		intron	N/A	NP_001361707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FECH	ENST00000262093.11	TSL:1 MANE Select	c.464-1627C>T		intron	N/A	ENSP00000262093.6
	FECH	ENST00000652755.1		c.482-1627C>T		intron	N/A	ENSP00000498358.1
	FECH	ENST00000382873.8	TSL:2	c.248-1627C>T		intron	N/A	ENSP00000372326.4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16581 AN: 152020 Hom.: 1323 Cov.: 33

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.109 AC: 16607 AN: 152138 Hom.: 1326 Cov.: 33 AF XY: 0.113 AC XY: 8388 AN XY: 74362

African (AFR) AF: 0.0682 AC: 2829 AN: 41508

American (AMR) AF: 0.240 AC: 3667 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1704 AN: 5168

South Asian (SAS) AF: 0.129 AC: 624 AN: 4828

European-Finnish (FIN) AF: 0.0811 AC: 857 AN: 10570

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6298 AN: 67992

Other (OTH) AF: 0.135 AC: 284 AN: 2110

Alfa AF: 0.100 Hom.: 586

Bravo AF: 0.121

Asia WGS AF: 0.212 AC: 735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.81
PhyloP100		-0.14
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: rs2269221; hg19: chr18-55235440;