rs763601207
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000143.4(FH):āc.587A>Gā(p.His196Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,322 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H196Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000143.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FH | NM_000143.4 | c.587A>G | p.His196Arg | missense_variant | 5/10 | ENST00000366560.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FH | ENST00000366560.4 | c.587A>G | p.His196Arg | missense_variant | 5/10 | 1 | NM_000143.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251158Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135740
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461322Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726998
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2015 | The p.H196R variant (also known as c.587A>G and p.H153R), located in coding exon 5 of the FH gene, results from an A to G substitution at nucleotide position 587. The histidine at codon 196 is replaced by arginine, an amino acid with highly similar properties. This variant is referred to as p.H153R in this paper and was seen in an individual who was diagnosed with a malignant uterine leiomyosarcoma at 30 and had had two additional myomectomies by age 32 (Kiuru M, et al. Cancer Res. 2002 Aug; 62(16):4554-7). In two additional papers, this alteration was detected in several individuals with either uterine leiomyosarcoma(s), renal cell cancer, and/or leiomyomas; however, individual phenotypic information was not provided (Lehtonen HJ, et al. J. Med. Genet. 2006 Jun; 43(6):523-6, Mäkinen N, et al. Eur. J. Hum. Genet. 2013 Nov; 21(11):1300-3). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 4500 alleles tested) in our clinical cohort. 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 p.H196R remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at