rs76963591

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• retinal macular dystrophy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 41

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy 12

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.0211 AC: 3360 AN: 159262 AF XY: 0.0217

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 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

African (AFR) AF: 0.0592 AC: 1695 AN: 28654

American (AMR) AF: 0.0161 AC: 469 AN: 29142

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 671 AN: 22690

East Asian (EAS) AF: 0.00227 AC: 79 AN: 34864

South Asian (SAS) AF: 0.0326 AC: 2098 AN: 64264

European-Finnish (FIN) AF: 0.00700 AC: 342 AN: 48844

Middle Eastern (MID) AF: 0.0404 AC: 215 AN: 5320

European-Non Finnish (NFE) AF: 0.0222 AC: 23304 AN: 1049608

Other (OTH) AF: 0.0291 AC: 1594 AN: 54726

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

African (AFR) AF: 0.0694 AC: 2875 AN: 41454

American (AMR) AF: 0.0269 AC: 411 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5180

South Asian (SAS) AF: 0.0372 AC: 179 AN: 4806

European-Finnish (FIN) AF: 0.00627 AC: 66 AN: 10528

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1563 AN: 67966

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

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

Nov 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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.

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
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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