rs3848519

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/20 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:8

Conservation

PhyloP100: 0.874

Publications

17 publications found

Variant links:

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

FECH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5 link	c.163G>T	p.Gly55Cys	missense_variant	Exon 2 of 11	ENST00000262093.11	NP_000131.2	P22830-1Q7KZA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FECH	ENST00000262093.11 link	c.163G>T	p.Gly55Cys	missense_variant	Exon 2 of 11	1	NM_000140.5	ENSP00000262093.6		P22830-1

Frequencies

GnomAD3 genomes

AF:

0.0203

AC:

3083

AN:

152012

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0221

AC:

5548

AN:

251472

AF XY:

0.0229

show subpopulations

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 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.:

AF XY:

0.0224

AC XY:

16299

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0151

AC:

505

AN:

33476

American (AMR)

AF:

0.0271

AC:

1210

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26136

East Asian (EAS)

AF:

0.0115

AC:

455

AN:

39700

South Asian (SAS)

AF:

0.0461

AC:

3976

AN:

86250

European-Finnish (FIN)

AF:

0.0178

AC:

951

AN:

53414

Middle Eastern (MID)

AF:

0.0191

AC:

110

AN:

5746

European-Non Finnish (NFE)

AF:

0.0210

AC:

23326

AN:

1111998

Other (OTH)

AF:

0.0199

AC:

1200

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1900

3800

5700

7600

9500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0203

AC:

3081

AN:

152130

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1532

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0154

AC:

640

AN:

41506

American (AMR)

AF:

0.0340

AC:

519

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.0155

AC:

AN:

5174

South Asian (SAS)

AF:

0.0512

AC:

246

AN:

4802

European-Finnish (FIN)

AF:

0.0176

AC:

186

AN:

10568

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1244

AN:

68008

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

155

310

466

621

776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0190

Hom.:

Bravo

AF:

0.0204

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.0184

AC:

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:1Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FECH: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Protoporphyria, erythropoietic, 1

Pathogenic:1Benign:2

Dec 16, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.66

T;T;T;.

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Uncertain

-0.0087

MutationAssessor

Benign

0.0

N;N;.;.

PhyloP100

0.87

PrimateAI

Benign

0.32

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

GERP RS

1.6

Varity_R

0.088

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs3848519

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over