rs149651434
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_000143.4(FH):āc.674T>Cā(p.Phe225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,534 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F225L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.674T>C | p.Phe225Ser | missense_variant | 5/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.674T>C | p.Phe225Ser | missense_variant | 5/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251274Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461534Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727074
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2023 | This variant has not been reported in the literature in individuals affected with FH-related conditions. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the FH protein (p.Phe225Ser). This variant is present in population databases (rs149651434, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 460372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2024 | The p.F225S variant (also known as c.674T>C), located in coding exon 5 of the FH gene, results from a T to C substitution at nucleotide position 674. The phenylalanine at codon 225 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 1/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at