rs2078622

Positions:

• chr4-16035729-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006017.3(PROM1):​c.303+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,956 control chromosomes in the GnomAD database, including 217,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14768 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202539 hom.)
• Consequence: PROM1 NM_006017.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001957
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.700

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-16035729-C-T is Benign according to our data. Variant chr4-16035729-C-T is described in ClinVar as [Benign]. Clinvar id is 259906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16035729-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROM1	NM_006017.3	c.303+6G>A		splice_donor_region_variant, intron_variant		ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.303+6G>A		splice_donor_region_variant, intron_variant		1	NM_006017.3	ENSP00000415481	P3

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60374 AN: 151998 Hom.: 14761 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.451

GnomAD3 exomes AF: 0.449 AC: 111659 AN: 248760 Hom.: 27900 AF XY: 0.463 AC XY: 62513 AN XY: 134966

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.517 AC: 753858 AN: 1457840 Hom.: 202539 Cov.: 41 AF XY: 0.518 AC XY: 375526 AN XY: 725406

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.555

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.397 AC: 60376 AN: 152116 Hom.: 14768 Cov.: 33 AF XY: 0.394 AC XY: 29328 AN XY: 74356

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.551

Gnomad4 OTH AF: 0.455

Alfa AF: 0.524 Hom.: 40675

Bravo AF: 0.375

Asia WGS AF: 0.312 AC: 1085 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.559

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Stargardt disease 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinal macular dystrophy type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cone-rod dystrophy 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa 41 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.2
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.090		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: rs2078622; hg19: chr4-16037352; COSMIC: COSV71699244;