18-57559148-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000140.5(FECH):c.801G>A(p.Met267Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,602,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M267T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:1
• Conservation: PhyloP100: 5.45

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26054183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FECH	NM_000140.5	c.801G>A	p.Met267Ile	missense_variant	7/11	ENST00000262093.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FECH	ENST00000262093.11	c.801G>A	p.Met267Ile	missense_variant	7/11	1	NM_000140.5

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00104 AC: 261 AN: 251240 Hom.: 0 AF XY: 0.00110 AC XY: 149 AN XY: 135788

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00126 AC: 1830 AN: 1450392 Hom.: 0 Cov.: 25 AF XY: 0.00125 AC XY: 900 AN XY: 722352

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74458

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 267 of the FECH protein (p.Met267Ile). This variant is present in population databases (rs118204037, gnomAD 0.2%). This missense change has been observed in individual(s) with erythropoietic protoporphyria (PMID: 1755842, 16385445, 29941360). ClinVar contains an entry for this variant (Variation ID: 549). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FECH protein function. Experimental studies have shown that this missense change affects FECH function (PMID: 8276828, 15574461). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 16, 1991	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.84
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.88	P;P
Vest4		0.79
MutPred		0.81		Loss of disorder (P = 0.0921);.;
MVP		0.98
MPC		0.94
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs118204037; hg19: chr18-55226380;