1-241497928-T-G
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4
The NM_000143.4(FH):c.1433A>C(p.Asn478Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N478S) has been classified as Likely benign.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary leiomyomatosis and renal cell cancerInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- fumaric aciduriaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
- pheochromocytoma-paragangliomaInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- leiomyosarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.1433A>C | p.Asn478Thr | missense_variant | Exon 10 of 10 | ENST00000366560.4 | NP_000134.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD2 exomes AF: 0.00000402 AC: 1AN: 248984 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461648Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727132 show subpopulations
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 478 of the FH protein (p.Asn478Thr). This variant is present in population databases (rs201886827, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 3230438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Fumarase deficiency Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.N478T variant (also known as c.1433A>C), located in coding exon 10 of the FH gene, results from an A to C substitution at nucleotide position 1433. The asparagine at codon 478 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at