4-16013299-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_006017.3(PROM1):c.1117C>T(p.Arg373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PROM1
NM_006017.3 missense
NM_006017.3 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 0.303
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 4-16013299-G-A is Pathogenic according to our data. Variant chr4-16013299-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16013299-G-A is described in Lovd as [Pathogenic]. Variant chr4-16013299-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-16013299-G-A is described in Lovd as [Pathogenic]. Variant chr4-16013299-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PROM1 | NM_006017.3 | c.1117C>T | p.Arg373Cys | missense_variant | 11/28 | ENST00000447510.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PROM1 | ENST00000447510.7 | c.1117C>T | p.Arg373Cys | missense_variant | 11/28 | 1 | NM_006017.3 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456900Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725068
GnomAD4 exome
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30
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1
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GnomAD4 genome
GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2024 | Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein mislocalization (PMID: 18654668); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28840994, 29847639, 12657606, 23161075, 25356976, 26667666, 25133751, 28559085, 32531858, 31144483, 31129250, 10205271, 25590640, 27624628, 28076437, 27160483, 26103963, 20393116, 28041643, 23891399, 31054281, 32820593, 32534057, 31736247, 32581362, 34008001, 33090715, 30653986, 22581970, 22183351, 20859302, 29555955, 36259723, 38072963, 36460718, 31213501, 36729443, 36819107, 36909829, 33749171, 36284460, 37734845, 30926958, 18654668) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | PROM1: PP1:Strong, PS4, PM2, PP4, PS3:Supporting, BP4 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 22, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the PROM1 protein (p.Arg373Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant forms of retinal dystrophy (PMID: 18654668, 20393116, 22183351, 28559085, 29847639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PROM1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROM1 function (PMID: 18654668). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:3
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinal macular dystrophy type 2 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
| Pathogenic, criteria provided, single submitter | research | Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Jul 24, 2023 | Clinical significance based on ACMG v2.0 - |
Stargardt disease 4 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
Macular dystrophy Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Cone-rod dystrophy 12 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
Stargardt disease Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Retinitis pigmentosa Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Arg373Cys variant in PROM1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Stargardt disease 4;C2675210:Cone-rod dystrophy 12;C2677516:Retinitis pigmentosa 41;C4749334:Retinal macular dystrophy type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;.;T;.
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;.;.;N
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
P;P;P;P;P;P
Vest4
MutPred
Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);.;.;Loss of MoRF binding (P = 0.0109);
MVP
MPC
0.018
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at