rs764466739
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000140.5(FECH):c.1136del(p.Lys379ArgfsTer21) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,454,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FECH
NM_000140.5 frameshift, splice_region
NM_000140.5 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.72
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-57551315-CT-C is Pathogenic according to our data. Variant chr18-57551315-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 558.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FECH | NM_000140.5 | c.1136del | p.Lys379ArgfsTer21 | frameshift_variant, splice_region_variant | 10/11 | ENST00000262093.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FECH | ENST00000262093.11 | c.1136del | p.Lys379ArgfsTer21 | frameshift_variant, splice_region_variant | 10/11 | 1 | NM_000140.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250976Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135680
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1454314Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 724014
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | ClinVar contains an entry for this variant (Variation ID: 558). This variant is also known as 1135AA ‚Üí A. This premature translational stop signal has been observed in individual(s) with protoporphyric liver disease (PMID: 9649563). This variant is present in population databases (rs764466739, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys379Argfs*21) in the FECH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the FECH protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FECH protein in which other variant(s) (p.Cys406Tyr) have been determined to be pathogenic (PMID: 10942404; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. - |
Protoporphyria, erythropoietic, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1998 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at