rs3848519

chr18-57580104-C-Achr18-57580104-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000140.5(FECH):c.163G>T(p.Gly55Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,968 control chromosomes in the GnomAD database, including 508 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. G55S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.020 (55 hom., cov: 32)
  • Exomes 𝑓: 0.022 (453 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: 0.874

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002217114).
• BP6: Variant 18-57580104-C-A is Benign according to our data. Variant chr18-57580104-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}. Variant chr18-57580104-C-A is described in Lovd as [Benign]. Variant chr18-57580104-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0203 (3081/152130) while in subpopulation SAS AF= 0.0512 (246/4802). AF 95% confidence interval is 0.046. There are 55 homozygotes in gnomad4. There are 1532 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 55 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FECH	NM_000140.5	c.163G>T	p.Gly55Cys	missense_variant	2/11	ENST00000262093.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FECH	ENST00000262093.11	c.163G>T	p.Gly55Cys	missense_variant	2/11	1	NM_000140.5

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3083 AN: 152012 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0221 AC: 5548 AN: 251472 Hom.: 98 AF XY: 0.0229 AC XY: 3112 AN XY: 135918

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0172

Gnomad SAS exome AF: 0.0456

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0218 AC: 31846 AN: 1461838 Hom.: 453 Cov.: 32 AF XY: 0.0224 AC XY: 16299 AN XY: 727216

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.0271

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0461

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0210

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0203 AC: 3081 AN: 152130 Hom.: 55 Cov.: 32 AF XY: 0.0206 AC XY: 1532 AN XY: 74370

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.0512

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0179 Hom.: 55

Bravo AF: 0.0204

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.0183 AC: 157

ExAC AF: 0.0222 AC: 2693

EpiCase AF: 0.0194

EpiControl AF: 0.0183

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2022	BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	FECH: BS1, BS2 -

Protoporphyria, erythropoietic, 1 Pathogenic:1 Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 16, 1991	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 4.7% in South Asian with 37 homozygotes -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	13
Dann	Benign	0.49
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.66	T;T;T;.
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Uncertain	-0.0087	T
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.56	N;N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.17	T;T;.;.
Sift4G	Uncertain	0.041	D;T;.;T
Polyphen		0.21	B;D;.;.
Vest4		0.15
MPC		0.72
ClinPred		0.0056	T
GERP RS		1.6
Varity_R		0.088

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: rs3848519; hg19: chr18-55247336; COSMIC: COSV50490775;