rs34269395

Variant names:

• chr4-15980540-A-AG
• rs34269395
• NM_006017.3:c.2374-4dupC

Your query was ambiguous. Multiple possible variants found:

• chr4-15980540-A-AG
• chr4-15980540-A-AGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006017.3(PROM1):​c.2374-4dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,485,620 control chromosomes in the GnomAD database, including 51,835 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6655 hom., cov: 0)
  • Exomes 𝑓: 0.26 (45180 hom.)
• Consequence: PROM1 NM_006017.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.539
• Publications: 10 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 -16 ACMG points.

• BP6: Variant 4-15980540-A-AG is Benign according to our data. Variant chr4-15980540-A-AG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.339 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.2374-4dupC		splice_region intron	N/A	NP_006008.1
	PROM1	NM_001145847.2		c.2347-4dupC		splice_region intron	N/A	NP_001139319.1
	PROM1	NM_001145848.2		c.2347-4dupC		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.2374-4dupC		splice_region intron	N/A	ENSP00000415481.2
	PROM1	ENST00000505450.5	TSL:1	c.2347-4dupC		splice_region intron	N/A	ENSP00000426090.1
	PROM1	ENST00000508167.5	TSL:1	c.2347-4dupC		splice_region intron	N/A	ENSP00000427346.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44022 AN: 150920 Hom.: 6657 Cov.: 0

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.359

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.282 AC: 41237 AN: 146440 AF XY: 0.278

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.343

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.256 AC: 341110 AN: 1334584 Hom.: 45180 Cov.: 26 AF XY: 0.256 AC XY: 169101 AN XY: 660612

African (AFR) AF: 0.341 AC: 10217 AN: 29962

American (AMR) AF: 0.328 AC: 11290 AN: 34414

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6056 AN: 24648

East Asian (EAS) AF: 0.304 AC: 10730 AN: 35278

South Asian (SAS) AF: 0.249 AC: 18764 AN: 75498

European-Finnish (FIN) AF: 0.234 AC: 11475 AN: 48972

Middle Eastern (MID) AF: 0.302 AC: 1680 AN: 5554

European-Non Finnish (NFE) AF: 0.250 AC: 255869 AN: 1024418

Other (OTH) AF: 0.269 AC: 15029 AN: 55840

GnomAD4 genome AF: 0.292 AC: 44029 AN: 151036 Hom.: 6655 Cov.: 0 AF XY: 0.294 AC XY: 21696 AN XY: 73748

African (AFR) AF: 0.340 AC: 13914 AN: 40978

American (AMR) AF: 0.347 AC: 5262 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1735 AN: 5146

South Asian (SAS) AF: 0.262 AC: 1260 AN: 4808

European-Finnish (FIN) AF: 0.229 AC: 2357 AN: 10306

Middle Eastern (MID) AF: 0.341 AC: 99 AN: 290

European-Non Finnish (NFE) AF: 0.263 AC: 17842 AN: 67864

Other (OTH) AF: 0.293 AC: 615 AN: 2096

Alfa AF: 0.235 Hom.: 922

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jun 07, 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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stargardt Disease, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Macular dystrophy, retinal Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-Rod Dystrophy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
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: rs34269395; hg19: chr4-15982163;