rs794726694
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_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 ).
Frequency
Genomes: not found (cov: 31)
Exomes π: 0.0000069 ( 1 hom. )
Consequence
PROP1
NM_006261.5 frameshift, splice_region
NM_006261.5 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.78
Genes affected
PROP1 (HGNC:9455): (PROP paired-like homeobox 1) This gene encodes a paired-like homeodomain transcription factor in the developing pituitary gland. Expression occurs prior to and is required for expression of pou domain transcription factor 1, which is responsible for pituitary development and hormone expression. Mutations in this gene have been associated with combined pituitary hormone deficiency-2 as well as deficiencies in luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, and thyroid-stimulating hormone. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.836 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-177994323-GGTGGAGCACTCGA-G is Pathogenic according to our data. Variant chr5-177994323-GGTGGAGCACTCGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 8101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROP1 | NM_006261.5 | c.112_124del | p.Ser38ProfsTer123 | frameshift_variant, splice_region_variant | 2/3 | ENST00000308304.2 | NP_006252.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PROP1 | ENST00000308304.2 | c.112_124del | p.Ser38ProfsTer123 | frameshift_variant, splice_region_variant | 2/3 | 1 | NM_006261.5 | ENSP00000311290 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000444 AC: 1AN: 225024Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 122260
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GnomAD4 exome AF: 0.00000689 AC: 10AN: 1450900Hom.: 1 AF XY: 0.0000111 AC XY: 8AN XY: 720680
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GnomAD4 genome Cov.: 31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pituitary hormone deficiency, combined, 2 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2000 | - - |
Likely pathogenic, no assertion criteria provided | case-control | Endocrinology Clinic, Seth G.S. Medical College | Oct 31, 2013 | - - |
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 | Baylor Genetics | Oct 05, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at