rs761911901

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_006017.3(PROM1):c.1946C>T(p.Ser649Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,454,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S649P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

PROM1
NM_006017.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 1.67

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 Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 4-15991259-G-A is Pathogenic according to our data. Variant chr4-15991259-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425331.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=1}. Variant chr4-15991259-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.21574956). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROM1	NM_006017.3 linkuse as main transcript	c.1946C>T	p.Ser649Leu	missense_variant	18/28	ENST00000447510.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROM1	ENST00000447510.7 linkuse as main transcript	c.1946C>T	p.Ser649Leu	missense_variant	18/28	1	NM_006017.3	P3	O43490-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000290

AC:

AN:

241558

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131360

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:

0.000241

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1454502

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

723336

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:

0.000296

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20554613, Duignan2015[abstract], 28418496) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 27, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 649 of the PROM1 protein (p.Ser649Leu). This variant is present in population databases (rs761911901, gnomAD 0.02%). This missense change has been observed in individual(s) with cone-rod dystrophy and/or retinitis pigmentosa (PMID: 28418496, 32531858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 425331). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cone-rod dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Jan 09, 2020

- -

Cone-rod dystrophy 12

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jun 22, 2023

This heterozygous variant c.1946C>T (Ser649Leu) has been identified in a proband with features suggestive of cone rod dystrophy in compound heterozygous state with c.730C>T (p.Arg244Ter). -

Retinitis pigmentosa 41

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The c.1946C>T (p.Ser649Leu) missense variant in PROM1 gene has been submitted to ClinVar with varying interpretations: Pathogenic/Variant of Uncertain Significance (VUS). It has been reported in individuals affected with cone-rod dystrophy (Littink et al, 2010). The p.Ser649Leu variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ser at position 649 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ser649Leu in PROM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Stargardt disease 4;C2675210:Cone-rod dystrophy 12;C2677516:Retinitis pigmentosa 41;C4749334:Retinal macular dystrophy type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.70

D;.;.;.;.;D

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.89

D;D;D;.;D;.

M_CAP

Benign

0.0085

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;.;.;L

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Benign

0.055

Sift

Benign

0.071

T;T;T;T;T;T

Sift4G

Benign

0.082

T;T;T;T;T;T

Polyphen

0.055

B;B;B;B;B;B

Vest4

0.33

MutPred

0.61

Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);

MVP

0.64

MPC

0.017

ClinPred

0.058

GERP RS

0.77

Varity_R

0.073

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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