NM_001382289.1:c.236_237delTG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001382289.1(FSHB):c.236_237delTG(p.Val79GlufsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000558 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001382289.1 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FSHB | NM_001382289.1 | c.236_237delTG | p.Val79GlufsTer27 | frameshift_variant | Exon 3 of 3 | ENST00000533718.2 | NP_001369218.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FSHB | ENST00000533718.2 | c.236_237delTG | p.Val79GlufsTer27 | frameshift_variant | Exon 3 of 3 | 1 | NM_001382289.1 | ENSP00000433424.1 | ||
FSHB | ENST00000254122.8 | c.236_237delTG | p.Val79GlufsTer27 | frameshift_variant | Exon 3 of 3 | 5 | ENSP00000254122.3 | |||
FSHB | ENST00000417547.1 | c.236_237delTG | p.Val79GlufsTer27 | frameshift_variant | Exon 3 of 3 | 5 | ENSP00000416606.1 | |||
ARL14EP-DT | ENST00000662729.1 | n.293-76793_293-76792delAC | intron_variant | Intron 3 of 4 |
Frequencies
GnomAD3 genomes AF: 0.0000985 AC: 15AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000957 AC: 24AN: 250876Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135548
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461742Hom.: 0 AF XY: 0.0000633 AC XY: 46AN XY: 727178
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74362
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 24 without anosmia Pathogenic:2
- -
The FSHB c.236_237delTG (p.Val79GlufsTer27) variant is a frameshift variant predicted to result in premature truncation of the protein. The p.Val79GlufsTer27 variant is reported in four studies in which it is found in a total of four individuals affected with follicle-stimulating hormone (FSH) deficiency, including in three in a homozygous state (Matthews et al. 1993; Matthews et al. 1997; Phillip et al. 1998) and in one in a compound heterozygous state (Layman et al. 1997). The p.Val79GlufsTer27 variant is also reported to be present in six unaffected family members in a heterozygous state (Matthews et al. 1993; Layman et al. 1997; Phillip et al. 1998). The variant is absent from 34 controls (Layman et al. 1997) but is reported at a frequency of 0.00224 in the Ashkenazi Jewish population of the Genome Aggregation Database. Transfection of the p.Val79GlufsTer27 variant into CHO cells, showed no expression of FSH (Layman et al. 1997). The predicted truncation eliminates the last five cysteine residues of the protein, which are believed to be important for dimer stabilization. Based on collective evidence, the p.Val79GlufsTer27 variant is classified as pathogenic for isolated follicle-stimulating hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided Pathogenic:2
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 51 amino acids are lost and replaced with 26 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 9624193, 8220432, 20488225, 9271483) -
DNA sequence analysis of the FSHB gene demonstrated a two base pair deletion in exon 3, c.236_237del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 26 amino acids downstream of the mutation, p.Val79Glufs*27. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FSHB protein with potentially abnormal function. This sequence change has previously been described in the homozygous state in a female patient with infertility, primary amenorrhea, with undetectable serum FSH (PMID: 8220432). This variant is also reported to occur in the compound heterozygous state with a pathogenic missense variant in another patient with similar features (PMID: 9271483). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at