rs780697796
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_006017.3(PROM1):c.436C>T(p.Arg146*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
PROM1
NM_006017.3 stop_gained
NM_006017.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.34
Genes affected
PROM1 (HGNC:9454): (prominin 1) This gene encodes a pentaspan transmembrane glycoprotein. The protein localizes to membrane protrusions and is often expressed on adult stem cells, where it is thought to function in maintaining stem cell properties by suppressing differentiation. Mutations in this gene have been shown to result in retinitis pigmentosa and Stargardt disease. Expression of this gene is also associated with several types of cancer. This gene is expressed from at least five alternative promoters that are expressed in a tissue-dependent manner. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 4-16033377-G-A is Pathogenic according to our data. Variant chr4-16033377-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 438214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16033377-G-A is described in Lovd as [Pathogenic]. Variant chr4-16033377-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-16033377-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROM1 | NM_006017.3 | c.436C>T | p.Arg146* | stop_gained | 5/28 | ENST00000447510.7 | NP_006008.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PROM1 | ENST00000447510.7 | c.436C>T | p.Arg146* | stop_gained | 5/28 | 1 | NM_006017.3 | ENSP00000415481.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249100Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135112
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727092
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 41 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 28, 2022 | This variant is present in population databases (rs780697796, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 438214). This premature translational stop signal has been observed in individuals with autosomal recessive PROM1-related conditions (PMID: 25356976, 28041643, 29555955). This sequence change creates a premature translational stop signal (p.Arg146*) in the PROM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROM1 are known to be pathogenic (PMID: 17605048, 19718270, 24154662, 25474345). - |
Retinal dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at