Genetic Variant FECH:p.Arg96Pro (chr18-57573273-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000140.5(FECH):c.287G>C(p.Arg96Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FECH
NM_000140.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.522

Publications

0 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal erythropoietic protoporphyria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FECH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.287G>C	p.Arg96Pro	missense	Exon 3 of 11	NP_000131.2	P22830-1
FECH	NM_001012515.4		c.305G>C	p.Arg102Pro	missense	Exon 3 of 11	NP_001012533.1	P22830-2
FECH	NM_001374778.1		c.287G>C	p.Arg96Pro	missense	Exon 3 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.287G>C	p.Arg96Pro	missense	Exon 3 of 11	ENSP00000262093.6	P22830-1
FECH	ENST00000652755.1		c.305G>C	p.Arg102Pro	missense	Exon 3 of 11	ENSP00000498358.1	P22830-2
FECH	ENST00000878110.1		c.287G>C	p.Arg96Pro	missense	Exon 3 of 10	ENSP00000548169.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461336

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111494

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.097

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.097

MutationAssessor

Benign

-0.48

PhyloP100

0.52

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.52

Sift

Benign

0.16

Sift4G

Benign

0.27

Polyphen

0.019

Vest4

0.58

MutPred

0.42

Loss of sheet (P = 0.0817)

MVP

0.79

MPC

0.60

ClinPred

0.93

GERP RS

4.4

Varity_R

0.81

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over