18-57573273-C-G

Variant names:

• chr18-57573273-C-G
• rs1041951
• NM_000140.5:c.287G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000140.5(FECH):​c.287G>C​(p.Arg96Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.522
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 11	ENST00000262093.11	NP_000131.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11	c.287G>C	p.Arg96Pro	missense_variant	Exon 3 of 11	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461336 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727036

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111494

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;.;D;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.97	D;D;D;.;.
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	0.097	D
MutationAssessor	Benign	-0.48	N;.;.;.;.
PhyloP100		0.52
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.8	D;D;.;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.16	T;T;.;.;.
Sift4G	Benign	0.27	T;T;.;.;T
Polyphen		0.019	B;B;.;.;.
Vest4		0.58
MutPred		0.42		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.79
MPC		0.60
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.81
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1041951; hg19: chr18-55240505;