rs121909658
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PS1_ModeratePP3PP5BP4
The NM_000145.4(FSHR):c.566C>T(p.Ala189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_000145.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FSHR | NM_000145.4 | c.566C>T | p.Ala189Val | missense_variant | 7/10 | ENST00000406846.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FSHR | ENST00000406846.7 | c.566C>T | p.Ala189Val | missense_variant | 7/10 | 1 | NM_000145.4 | P1 | |
ENST00000634588.1 | n.492+36720G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000559 AC: 85AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000692 AC: 174AN: 251362Hom.: 0 AF XY: 0.000670 AC XY: 91AN XY: 135836
GnomAD4 exome AF: 0.000250 AC: 365AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.000248 AC XY: 180AN XY: 727216
GnomAD4 genome ? AF: 0.000559 AC: 85AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000888 AC XY: 66AN XY: 74338
ClinVar
Submissions by phenotype
Ovarian dysgenesis 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_000145.3:c.566C>T in the FSHR gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. The p.Ala189Val (NM_000145.3:c.566C>T) variant in FSHR has been reported as founder mutation in Finnish population(PMID: 11754099), and segregated in over 10 affected siblings in 6 families (PMID: 7553856). Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor (PMID: 7553856). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS4, PP3, PS3, PP1_Strong. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at