Genetic Variant FECH:p.Gly55Ser (chr18-57580104-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000140.5(FECH):c.163G>A(p.Gly55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,984 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G55C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

FECH
NM_000140.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

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, ClinGen, Laboratory for Molecular Medicine, 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041987896).

BP6

Variant 18-57580104-C-T is Benign according to our data. Variant chr18-57580104-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599190.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00233 (354/152132) while in subpopulation AFR AF = 0.00826 (343/41504). AF 95% confidence interval is 0.00754. There are 3 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000140.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FECH	NM_000140.5	MANE Select	c.163G>A	p.Gly55Ser	missense	Exon 2 of 11	NP_000131.2	P22830-1
FECH	NM_001012515.4		c.163G>A	p.Gly55Ser	missense	Exon 2 of 11	NP_001012533.1	P22830-2
FECH	NM_001374778.1		c.163G>A	p.Gly55Ser	missense	Exon 2 of 10	NP_001361707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FECH	ENST00000262093.11	TSL:1 MANE Select	c.163G>A	p.Gly55Ser	missense	Exon 2 of 11	ENSP00000262093.6	P22830-1
FECH	ENST00000652755.1		c.163G>A	p.Gly55Ser	missense	Exon 2 of 11	ENSP00000498358.1	P22830-2
FECH	ENST00000878110.1		c.163G>A	p.Gly55Ser	missense	Exon 2 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00826

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000704

AC:

177

AN:

251472

AF XY:

0.000471

show subpopulations

Gnomad AFR exome

AF:

0.00960

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000293

AC:

429

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

181

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0103

AC:

345

AN:

33476

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112010

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00233

AC:

354

AN:

152132

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00826

AC:

343

AN:

41504

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00000239

Hom.:

Bravo

AF:

0.00282

ExAC

AF:

0.000807

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

FECH-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.44

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.14

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.29

MutationAssessor

Benign

-1.6

PhyloP100

0.87

PrimateAI

Benign

0.31

PROVEAN

Benign

0.83

REVEL

Benign

0.25

Sift

Benign

0.63

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.041

MVP

0.58

MPC

0.39

ClinPred

0.0014

GERP RS

1.6

Varity_R

0.028

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over