NM_006017.3:c.2281-6C>G

Variant names:

• chr4-15984361-G-C
• rs3815344
• NM_006017.3:c.2281-6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006017.3(PROM1):​c.2281-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,556,772 control chromosomes in the GnomAD database, including 47,813 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3874 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43939 hom.)
• Consequence: PROM1 NM_006017.3 splice_region, intron
• Scores: Splicing: ADA: 0.2205
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.622
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-15984361-G-C is Benign according to our data. Variant chr4-15984361-G-C is described in ClinVar as Benign. ClinVar VariationId is 95330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006017.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	NM_006017.3	MANE Select	c.2281-6C>G		splice_region intron	N/A	NP_006008.1
	PROM1	NM_001145847.2		c.2254-6C>G		splice_region intron	N/A	NP_001139319.1
	PROM1	NM_001145848.2		c.2254-6C>G		splice_region intron	N/A	NP_001139320.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	ENST00000447510.7	TSL:1 MANE Select	c.2281-6C>G		splice_region intron	N/A	ENSP00000415481.2
	PROM1	ENST00000505450.5	TSL:1	c.2254-6C>G		splice_region intron	N/A	ENSP00000426090.1
	PROM1	ENST00000508167.5	TSL:1	c.2254-6C>G		splice_region intron	N/A	ENSP00000427346.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31162 AN: 151984 Hom.: 3879 Cov.: 32

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.242 AC: 50071 AN: 207112 AF XY: 0.243

Gnomad AFR exome AF: 0.0611

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.246 AC: 345650 AN: 1404670 Hom.: 43939 Cov.: 28 AF XY: 0.246 AC XY: 171559 AN XY: 696292

African (AFR) AF: 0.0636 AC: 2023 AN: 31808

American (AMR) AF: 0.319 AC: 12195 AN: 38242

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6121 AN: 24600

East Asian (EAS) AF: 0.0926 AC: 3558 AN: 38436

South Asian (SAS) AF: 0.218 AC: 16828 AN: 77244

European-Finnish (FIN) AF: 0.236 AC: 12257 AN: 51854

Middle Eastern (MID) AF: 0.294 AC: 1635 AN: 5554

European-Non Finnish (NFE) AF: 0.257 AC: 276827 AN: 1078788

Other (OTH) AF: 0.244 AC: 14206 AN: 58144

GnomAD4 genome AF: 0.205 AC: 31145 AN: 152102 Hom.: 3874 Cov.: 32 AF XY: 0.208 AC XY: 15481 AN XY: 74348

African (AFR) AF: 0.0690 AC: 2864 AN: 41522

American (AMR) AF: 0.315 AC: 4812 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 801 AN: 3470

East Asian (EAS) AF: 0.118 AC: 612 AN: 5176

South Asian (SAS) AF: 0.208 AC: 1002 AN: 4816

European-Finnish (FIN) AF: 0.236 AC: 2491 AN: 10574

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17846 AN: 67972

Other (OTH) AF: 0.230 AC: 485 AN: 2106

Alfa AF: 0.220 Hom.: 1274

Bravo AF: 0.200

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 20, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stargardt disease 4 Benign:2

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.

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal macular dystrophy type 2 Benign:2

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.

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-rod dystrophy 12 Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 41 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.0
DANN	Benign	0.50
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.19		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: rs3815344; hg19: chr4-15985984; COSMIC: COSV71699487; COSMIC: COSV71699487;