chr18-57580222-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000140.5(FECH):c.68-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,044 control chromosomes in the GnomAD database, including 38,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.27 ( 6866 hom., cov: 32)

Exomes 𝑓: 0.19 ( 31549 hom. )

Consequence

FECH
NM_000140.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.509

Publications

13 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 (BayesDel_noAF=-0.81).

BP6

Variant 18-57580222-G-A is Benign according to our data. Variant chr18-57580222-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 550.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5 link	c.68-23C>T		intron_variant	Intron 1 of 10	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.68-23C>T		intron_variant	Intron 1 of 10	1	NM_000140.5	ENSP00000262093.6		P22830-1

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41599

AN:

151926

Hom.:

6851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.447

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.170

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.251

AC:

62889

AN:

250832

AF XY:

0.240

show subpopulations

Gnomad AFR exome

AF:

0.448

Gnomad AMR exome

AF:

0.416

Gnomad ASJ exome

AF:

0.218

Gnomad EAS exome

AF:

0.311

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.217

GnomAD4 exome

AF:

0.194

AC:

283768

AN:

1461000

Hom.:

31549

Cov.:

AF XY:

0.194

AC XY:

141175

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.454

AC:

15194

AN:

33452

American (AMR)

AF:

0.398

AC:

17798

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5868

AN:

26130

East Asian (EAS)

AF:

0.366

AC:

14537

AN:

39694

South Asian (SAS)

AF:

0.257

AC:

22140

AN:

86244

European-Finnish (FIN)

AF:

0.231

AC:

12327

AN:

53284

Middle Eastern (MID)

AF:

0.239

AC:

1376

AN:

5764

European-Non Finnish (NFE)

AF:

0.164

AC:

182079

AN:

1111368

Other (OTH)

AF:

0.206

AC:

12449

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

11291

22582

33873

45164

56455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6904

13808

20712

27616

34520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.274

AC:

41673

AN:

152044

Hom.:

6866

Cov.:

AF XY:

0.278

AC XY:

20647

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.447

AC:

18527

AN:

41448

American (AMR)

AF:

0.303

AC:

4622

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

744

AN:

3468

East Asian (EAS)

AF:

0.324

AC:

1673

AN:

5164

South Asian (SAS)

AF:

0.251

AC:

1210

AN:

4816

European-Finnish (FIN)

AF:

0.246

AC:

2596

AN:

10568

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.170

AC:

11584

AN:

67988

Other (OTH)

AF:

0.262

AC:

553

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1456

2912

4367

5823

7279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.205

Hom.:

13583

Bravo

AF:

0.288

Asia WGS

AF:

0.294

AC:

1020

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Protoporphyria, erythropoietic, 1

Pathogenic:1Uncertain:1Benign:4

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2021

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PS5,BS2,BP6,BP7 -

Jan 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely benign. -

Apr 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 8280787, 1729699, 27884173, 26789144) -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jaundice;C0041834:Erythema

Benign:1

Jan 25, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.0

(source)

DANN

Benign

0.51

PhyloP100

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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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