rs543698823

Positions:

• chr4-16006637-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006017.3(PROM1):​c.1354dupT​(p.Tyr452fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000331 in 1,612,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. YY452F?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: PROM1 NM_006017.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 6.60

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]

ACMG classification

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 4-16006637-T-TA is Pathogenic according to our data. Variant chr4-16006637-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372711.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
PROM1	NM_006017.3	c.1354dupT	p.Tyr452fs	frameshift_variant	13/28	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.1354dupT	p.Tyr452fs	frameshift_variant	13/28	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 151932 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000220 AC: 54 AN: 245996 Hom.: 0 AF XY: 0.000225 AC XY: 30 AN XY: 133438

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000359

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000343 AC: 501 AN: 1460438 Hom.: 0 Cov.: 30 AF XY: 0.000381 AC XY: 277 AN XY: 726338

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000414

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000217 AC: 33 AN: 151932 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74180

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000238

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 12 Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Tyr452LeufsTer13 variant in PROM1 was identified by our study in one individual with cone-rod dystrophy. The p.Tyr452LeufsTer13 variant in PROM1 has been previously reported in 7 unrelated individuals with PROM1-associated retinopathy (PMID: 28041643, PMID: 19718270, PMID: 24154662, PMID: 26103963, PMID: 27874104, PMID: 25999674) and segregated with disease in 3 affected relatives from one family (PMID: 19718270) but has been identified in 0.05% (8/15262) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs543698823). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 7 previously reported unrelated individuals with PROM1-associated retinopathy (PMID: 28041643, PMID: 19718270, PMID: 24154662, PMID: 26103963, PMID: 27874104, PMID: 25999674), 3 were homozygotes (PMID: 19718270, PMID: 26103963, PMID: 27874104) and 3 were compound heterozygotes who carried pathogenic or likely pathogenic variants with unknown phase (PMID: 28041643, ClinVar Variation ID: 236527; PMID: 24154662, ClinVar Variation ID: 438215; PMID: 26103963, NC_000004.12:g.16006536A>G), which increases the likelihood that the p.Tyr452LeufsTer13 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 372711) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 452 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PROM1 gene is an established disease mechanism in autosomal recessive PROM1-associated retinal disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive neuronal PROM1-associated retinal disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Dec 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 25, 2022	This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PM3, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Retinal dystrophy Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 15, 2017	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 05, 2022	- -

Retinitis pigmentosa 41 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The PROM1 c.1354dup variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-M. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19718270, 24154662, 27874104, 25472526) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PROM1: PVS1, PM3:Strong, PM2, PP1:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Tyr452Leufs*13) 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 (rs543698823, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cone-rod dystrophy, or retinal disease (PMID: 19718270, 24154662, 27874104, 28041643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372711). For these reasons, this variant has been classified as Pathogenic. -

PROM1-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 21, 2024	The PROM1 c.1354dupT variant is predicted to result in a frameshift and premature protein termination (p.Tyr452Leufs*13). This variant has been reported many times in the homozygous and compound heterozygous states in individuals with retinal dystrophy (see for examples: referred to as c.1349insT in Pras et al. 2009. PubMed ID: 19718270; referred to as c.1354_1355insT in Wang et al. 2014. PubMed ID: 24154662). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PROM1 are an established mechanism of disease. Given the evidence, we interpret this variant as pathogenic for autosomal recessive disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PROM1 c.1354dupT (p.Tyr452LeufsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Tyr452LeufsTer13 variant has been reported in at least five studies in a total of six individuals with PROM1-related disorders, including two homozygotes and one presumed compound heterozygote with cone or cone-rod dystrophy, and in one homozygote, one presumed compound heterozygote, and one heterozygote with retinitis pigmentosa (Pras et al. 2009; Wang et al. 2014; van Huet et al. 2015; Boulanger-Scemama et al. 2015; Habibi et al. 2016). The p.Tyr452LeufsTer13 variant was absent from 100 controls and is reported with a frequency of 0.00026 in the European (non-Finnish) population from the Exome Aggregation Consortium. While some variants in the PROM1 gene have been associated with both autosomal dominant and autosomal recessive PROM1-related disorders, review of the available literature reveals that this variant appears to be contributing to an autosomal recessive mode of inheritance for cone/cone-rod dystrophy and retinitis pigmentosa. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr452LeufsTer13 is classified as likely pathogenic for PROM1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Autosomal recessive retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Nov 22, 2016

- -

Cone-rod dystrophy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

-

- -

Stargardt disease Pathogenic:1

Pathogenic, no assertion criteria provided

research

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Dec 14, 2022

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs543698823; hg19: chr4-16008260;