NM_000140.5:c.854A>G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000140.5(FECH):āc.854A>Gā(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 (ā ā ).
Frequency
Consequence
NM_000140.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Protoporphyria, erythropoietic, 1 Pathogenic:2
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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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at