4-16025199-GT-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_006017.3(PROM1):βc.622delβ(p.Thr208LeufsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 33)
Exomes π: 0.000038 ( 0 hom. )
Consequence
PROM1
NM_006017.3 frameshift
NM_006017.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.555
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]
Genome browser will be placed here
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 4-16025199-GT-G is Pathogenic according to our data. Variant chr4-16025199-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16025199-GT-G is described in Lovd as [Pathogenic]. Variant chr4-16025199-GT-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROM1 | NM_006017.3 | c.622del | p.Thr208LeufsTer23 | frameshift_variant | 6/28 | ENST00000447510.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROM1 | ENST00000447510.7 | c.622del | p.Thr208LeufsTer23 | frameshift_variant | 6/28 | 1 | NM_006017.3 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
6
AN:
152226
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249108Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135148
GnomAD3 exomes
AF:
AC:
8
AN:
249108
Hom.:
AF XY:
AC XY:
6
AN XY:
135148
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461420Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21AN XY: 726978
GnomAD4 exome
AF:
AC:
55
AN:
1461420
Hom.:
Cov.:
30
AF XY:
AC XY:
21
AN XY:
726978
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74494
GnomAD4 genome
AF:
AC:
6
AN:
152344
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74494
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
1
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 41 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 19, 2016 | The c.622delA (p.Thr208Leufs*23) frame-shift variant in the PROM1 gene was previously seen in a patient with arRP as a compound heterozygote with another frame-shift variant further downstream (amino acid position: 453) (Zhao L. et al. 2015). Furthermore, a homozygous frameshift variant in exon 8 of the PROM1gene was shown to co-segregate with arRP (Permanyer J. et al., 2010). Because there are 26 exons in this gene, this evidence suggests that truncating variants that result in loss-of-function is a mechanism of disease. The frequency of the variant in the population databases (1000 Genomes, Exome Sequencing Project and ExAC) is either absent, or below the frequency for the disease-allele. Therefore, this collective evidence supports the classification of the c.622delA (p.Thr208Leufs*23) as a Likely Pathogenic variant in PROM1. We have confirmed this finding in our laboratory using Sanger sequencing. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Thr208Leufs*23) 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). This variant is present in population databases (rs766246531, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive retinal disease (PMID: 25472526, 31129250). ClinVar contains an entry for this variant (Variation ID: 402237). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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