rs794726694
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006261.5(PROP1):βc.112_124delβ(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 (β β ). Synonymous variant affecting the same amino acid position (i.e. S38S) has been classified as Likely benign.
Frequency
Consequence
NM_006261.5 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROP1 | NM_006261.5 | c.112_124del | p.Ser38ProfsTer123 | frameshift_variant, splice_region_variant | 2/3 | ENST00000308304.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROP1 | ENST00000308304.2 | c.112_124del | p.Ser38ProfsTer123 | frameshift_variant, splice_region_variant | 2/3 | 1 | NM_006261.5 | P1 |
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
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Likely pathogenic, no assertion criteria provided | case-control | Endocrinology Clinic, Seth G.S. Medical College | Oct 31, 2013 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Possible founder variant on Indian subcontinent [Turton et al 2005] - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | 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