rs1131691243
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000143.4(FH):c.739G>T(p.Glu247Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E247E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000143.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.739G>T | p.Glu247Ter | stop_gained, splice_region_variant | 6/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.739G>T | p.Glu247Ter | stop_gained, splice_region_variant | 6/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458138Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 725502
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2018 | This sequence change creates a premature translational stop signal (p.Glu247*) in the FH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FH-related disease. ClinVar contains an entry for this variant (Variation ID: 429182). Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2015 | The p.E247* pathogenic mutation (also known as c.739G>T), located in coding exon 6 of the FH gene, results from a G to T substitution at nucleotide position 739. This change occurs in the first base pair of coding exon 6 and changes the amino acid from a glutamic acid to a stop codon at codon 247. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at