rs10033189

Positions:

• chr4-16075892-G-A
• chr4-16075892-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006017.3(PROM1):​c.15C>T​(p.Leu5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,088 control chromosomes in the GnomAD database, including 1,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (487 hom., cov: 32)
  • Exomes 𝑓: 0.024 (785 hom.)
• Consequence: PROM1 NM_006017.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-16075892-G-A is Benign according to our data. Variant chr4-16075892-G-A is described in ClinVar as [Benign]. Clinvar id is 259904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16075892-G-A is described in Lovd as [Benign]. Variant chr4-16075892-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROM1	NM_006017.3	c.15C>T	p.Leu5=	synonymous_variant	2/28	ENST00000447510.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROM1	ENST00000447510.7	c.15C>T	p.Leu5=	synonymous_variant	2/28	1	NM_006017.3	P3

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 8769 AN: 152100 Hom.: 486 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0377

GnomAD3 exomes AF: 0.0275 AC: 6731 AN: 244512 Hom.: 218 AF XY: 0.0254 AC XY: 3372 AN XY: 132534

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00693

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0239 AC: 34849 AN: 1458870 Hom.: 785 Cov.: 30 AF XY: 0.0233 AC XY: 16923 AN XY: 725322

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00683

Gnomad4 FIN exome AF: 0.0449

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0278

GnomAD4 genome AF: 0.0578 AC: 8794 AN: 152218 Hom.: 487 Cov.: 32 AF XY: 0.0580 AC XY: 4316 AN XY: 74434

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0470

Gnomad4 NFE AF: 0.0245

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0262 Hom.: 176

Bravo AF: 0.0580

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Stargardt disease 4 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. -

Retinal macular dystrophy type 2 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. -

Cone-rod dystrophy 12 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. -

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	-0.82
CADD	Benign	0.59
DANN	Benign	0.50

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: rs10033189; hg19: chr4-16077515; COSMIC: COSV71699442; COSMIC: COSV71699442;