NM_000140.5:c.463+2282A>C

Variant names:

• chr18-57569110-T-G
• rs533952
• NM_000140.5:c.463+2282A>C

Variant summary

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

The NM_000140.5(FECH):​c.463+2282A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 152,200 control chromosomes in the GnomAD database, including 43,943 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 0.75 (43943 hom., cov: 33)
• Consequence: FECH NM_000140.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 9 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 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.463+2282A>C		intron	N/A	NP_000131.2
	FECH	NM_001012515.4		c.481+2282A>C		intron	N/A	NP_001012533.1
	FECH	NM_001374778.1		c.463+2282A>C		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.463+2282A>C		intron	N/A	ENSP00000262093.6
	FECH	ENST00000652755.1		c.481+2282A>C		intron	N/A	ENSP00000498358.1
	FECH	ENST00000382873.8	TSL:2	c.247+2282A>C		intron	N/A	ENSP00000372326.4

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114611 AN: 152082 Hom.: 43908 Cov.: 33

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.725

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

GnomAD4 genome AF: 0.754 AC: 114704 AN: 152200 Hom.: 43943 Cov.: 33 AF XY: 0.749 AC XY: 55732 AN XY: 74390

African (AFR) AF: 0.881 AC: 36603 AN: 41544

American (AMR) AF: 0.735 AC: 11251 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2531 AN: 3468

East Asian (EAS) AF: 0.659 AC: 3410 AN: 5172

South Asian (SAS) AF: 0.781 AC: 3768 AN: 4826

European-Finnish (FIN) AF: 0.592 AC: 6266 AN: 10582

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48654 AN: 67994

Other (OTH) AF: 0.722 AC: 1525 AN: 2112

Alfa AF: 0.726 Hom.: 48737

Bravo AF: 0.765

Asia WGS AF: 0.713 AC: 2479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.0
DANN	Benign	0.74
PhyloP100		0.13
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: rs533952; hg19: chr18-55236342;