rs76963591

Variant names:

• chr4-16038994-C-T
• rs76963591
• NM_006017.3:c.228G>A

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.228G>A​(p.Leu76Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,490,096 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (148 hom., cov: 32)
  • Exomes 𝑓: 0.023 (441 hom.)
• Consequence: PROM1 NM_006017.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.432

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=-0.87).
• BP6: Variant 4-16038994-C-T is Benign according to our data. Variant chr4-16038994-C-T is described in ClinVar as [Benign]. Clinvar id is 95331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.432 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROM1	NM_006017.3	c.228G>A	p.Leu76Leu	synonymous_variant	Exon 3 of 28	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.228G>A	p.Leu76Leu	synonymous_variant	Exon 3 of 28	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5308 AN: 151868 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.00627

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0211 AC: 3360 AN: 159262 Hom.: 47 AF XY: 0.0217 AC XY: 1885 AN XY: 86934

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.00207

Gnomad SAS exome AF: 0.0315

Gnomad FIN exome AF: 0.00755

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0228 AC: 30467 AN: 1338112 Hom.: 441 Cov.: 29 AF XY: 0.0229 AC XY: 15101 AN XY: 659890

Gnomad4 AFR exome AF: 0.0592

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.0296

Gnomad4 EAS exome AF: 0.00227

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.00700

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0350 AC: 5318 AN: 151984 Hom.: 148 Cov.: 32 AF XY: 0.0342 AC XY: 2540 AN XY: 74276

Gnomad4 AFR AF: 0.0694

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0372

Gnomad4 FIN AF: 0.00627

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0290 Hom.: 37

Bravo AF: 0.0386

Asia WGS AF: 0.0310 AC: 107 AN: 3446

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cone-rod dystrophy 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.87
CADD	Benign	0.40
DANN	Benign	0.30

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: rs76963591; hg19: chr4-16040617; COSMIC: COSV71699385; COSMIC: COSV71699385;