rs370708663

chr18-57554903-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_000140.5(FECH):c.854A>G(p.Gln285Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: FECH NM_000140.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.43

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795
• PP5: Variant 18-57554903-T-C is Pathogenic according to our data. Variant chr18-57554903-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 327428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FECH	NM_000140.5	c.854A>G	p.Gln285Arg	missense_variant	8/11	ENST00000262093.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FECH	ENST00000262093.11	c.854A>G	p.Gln285Arg	missense_variant	8/11	1	NM_000140.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251386 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000708 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Protoporphyria, erythropoietic, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The FECH c.854A>G (p.Gln285Arg) variant has been reported in two studies in which it was found in three individuals from two families with erythropoietic protoporphyria (Holme et al. 2009; Mendez et al. 2009). The two related affected individuals are compound heterozygotes for the p.Gln285Arg variant and another missense variant and also carry the well-known hypomorphic FECH IVS3-48T>C variant on one allele. The third individual is homozygous for the p.Gln285Arg variant. The p.Gln285Arg variant was absent from 100 evaluated control individuals and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this frequency is based on one allele only in a region of good sequence coverage suggesting the variant is rare. Functional studies in prokaryotic cells indicate the p.Gln285Arg variant resulted in reduced protein activity of <1% of wild type (Holme et al. 2009; Mendez et al. 2009). Based on the collective evidence, the p.Gln285Arg variant is classified as likely pathogenic for erythropoietic protoporphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.94	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Pathogenic	0.77
Sift	Benign	0.27	T;T;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.75	P;P;.
Vest4		0.48
MVP		0.99
MPC		1.2
ClinPred		0.67	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66

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

LitVar

Other links and lift over

dbSNP: rs370708663; hg19: chr18-55222135;