rs587776682
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006261.5(PROP1):c.112_124delTCGAGTGCTCCAC(p.Ser38ProfsTer123) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,450,900 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_006261.5 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROP1 | NM_006261.5 | c.112_124delTCGAGTGCTCCAC | p.Ser38ProfsTer123 | frameshift_variant, splice_region_variant | Exon 2 of 3 | ENST00000308304.2 | NP_006252.4 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000444 AC: 1AN: 225024Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 122260
GnomAD4 exome AF: 0.00000689 AC: 10AN: 1450900Hom.: 1 AF XY: 0.0000111 AC XY: 8AN XY: 720680
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Pituitary hormone deficiency, combined, 2 Pathogenic:4Other:1
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Possible founder variant on Indian subcontinent [Turton et al 2005] -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser38Profs*123) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 189 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs587776682, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with pituitary hormone deficiency (PMID: 11134108, 15963055). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8101). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at