4-16000517-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_006017.3(PROM1):c.1557C>A(p.Tyr519Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000696 in 1,593,858 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: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

PROM1
NM_006017.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.464

Variant links:

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]

PROM1 links:

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 4-16000517-G-T is Pathogenic according to our data. Variant chr4-16000517-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 100577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16000517-G-T is described in Lovd as [Pathogenic]. Variant chr4-16000517-G-T is described in Lovd as [Likely_pathogenic]. Variant chr4-16000517-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROM1	NM_006017.3 linkuse as main transcript	c.1557C>A	p.Tyr519Ter	stop_gained	14/28	ENST00000447510.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROM1	ENST00000447510.7 linkuse as main transcript	c.1557C>A	p.Tyr519Ter	stop_gained	14/28	1	NM_006017.3	P3	O43490-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

247600

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000687

AC:

AN:

1441706

Hom.:

Cov.:

AF XY:

0.0000613

AC XY:

AN XY:

717964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000886

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000104

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	This sequence change creates a premature translational stop signal (p.Tyr519*) 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 (rs137853907, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with retinal dystrophy (PMID: 22025579, 28041643). ClinVar contains an entry for this variant (Variation ID: 100577). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 26, 2019	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Cone-rod dystrophy 12

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Tyr519Ter variant in PROM1 was identified by our study in one individual with cone-rod dystrophy. The p.Tyr519Ter variant in PROM1 has been previously reported in four unrelated individuals with PROM1-associated retinopathy (PMID: 32783370, PMID: 30926958, PMID: 28041643, PMID: 22025579) but has been identified in 0.015% (10/68036) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853907). 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 previously reported four unrelated individuals (PMID: 32783370, PMID: 30926958, PMID: 28041643, PMID: 22025579), one was a homozygote (PMID: 32783370) and one was a compound heterozygote who carried a reported pathogenic variant in trans (PMID: 30926958, ClinVar Variation ID: 253326), which increases the likelihood that the p.Tyr519Ter variant in PROM1 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 100577) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 519, which is 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 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.11

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

Vest4

0.97

GERP RS

-1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over