18-57573273-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000140.5(FECH):c.287G>A(p.Arg96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,052 control chromosomes in the GnomAD database, including 16,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1040 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15231 hom. )

Consequence

FECH
NM_000140.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.522

Publications

32 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036842525).

BP6

Variant 18-57573273-C-T is Benign according to our data. Variant chr18-57573273-C-T is described in ClinVar as Benign. ClinVar VariationId is 327434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FECH	NM_000140.5 link	c.287G>A	p.Arg96Gln	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 link	c.287G>A	p.Arg96Gln	missense_variant	Exon 3 of 11	1	NM_000140.5	ENSP00000262093.6

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16084

AN:

152106

Hom.:

1040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0912

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0937

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.101

AC:

25374

AN:

251432

AF XY:

0.100

show subpopulations

Gnomad AFR exome

AF:

0.0554

Gnomad AMR exome

AF:

0.0559

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.100

Gnomad NFE exome

AF:

0.154

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.136

AC:

198147

AN:

1459828

Hom.:

15231

Cov.:

AF XY:

0.133

AC XY:

96522

AN XY:

726364

show subpopulations

African (AFR)

AF:

0.0526

AC:

1759

AN:

33458

American (AMR)

AF:

0.0603

AC:

2696

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3278

AN:

26124

East Asian (EAS)

AF:

0.000378

AC:

AN:

39698

South Asian (SAS)

AF:

0.0284

AC:

2447

AN:

86248

European-Finnish (FIN)

AF:

0.104

AC:

5559

AN:

53410

Middle Eastern (MID)

AF:

0.0555

AC:

320

AN:

5762

European-Non Finnish (NFE)

AF:

0.157

AC:

174582

AN:

1110070

Other (OTH)

AF:

0.124

AC:

7491

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

7941

15883

23824

31766

39707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6018

12036

18054

24072

30090

<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:

0.106

AC:

16083

AN:

152224

Hom.:

1040

Cov.:

AF XY:

0.0999

AC XY:

7436

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0576

AC:

2391

AN:

41546

American (AMR)

AF:

0.0910

AC:

1392

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

405

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4818

European-Finnish (FIN)

AF:

0.0937

AC:

991

AN:

10578

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10482

AN:

68022

Other (OTH)

AF:

0.111

AC:

235

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

742

1483

2225

2966

3708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.131

Hom.:

4966

Bravo

AF:

0.102

TwinsUK

AF:

0.159

AC:

590

ALSPAC

AF:

0.153

AC:

590

ESP6500AA

AF:

0.0608

AC:

268

ESP6500EA

AF:

0.152

AC:

1311

ExAC

AF:

0.103

AC:

12496

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.151

EpiControl

AF:

0.140

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Protoporphyria, erythropoietic, 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;D;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.95

D;D;D;.;.

MetaRNN

Benign

0.0037

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.1

L;.;.;.;.

PhyloP100

0.52

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

N;N;.;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.27

T;T;.;.;.

Sift4G

Benign

0.44

T;T;.;.;T

Polyphen

0.12

B;B;.;.;.

Vest4

0.052

MPC

0.46

ClinPred

0.011

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

Mutation Taster

=97/3

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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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