4-15980543-A-G

Variant names:

• chr4-15980543-A-G
• rs6449209
• NM_006017.3:c.2374-6T>C

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.2374-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,437,758 control chromosomes in the GnomAD database, including 112,320 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 0.35 (8368 hom., cov: 30)
  • Exomes 𝑓: 0.40 (103952 hom.)
• Consequence: PROM1 NM_006017.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005700
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.601
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-15980543-A-G is Benign according to our data. Variant chr4-15980543-A-G is described in ClinVar as Benign. ClinVar VariationId is 95334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROM1	NM_006017.3	c.2374-6T>C		splice_region_variant, intron_variant	Intron 23 of 27	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.2374-6T>C		splice_region_variant, intron_variant	Intron 23 of 27	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.346 AC: 47674 AN: 137828 Hom.: 8362 Cov.: 30

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.391 AC: 52406 AN: 134186 AF XY: 0.391

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.396 AC: 514753 AN: 1299820 Hom.: 103952 Cov.: 22 AF XY: 0.394 AC XY: 254051 AN XY: 644264

African (AFR) AF: 0.166 AC: 4696 AN: 28284

American (AMR) AF: 0.333 AC: 10584 AN: 31744

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 9661 AN: 24090

East Asian (EAS) AF: 0.176 AC: 6133 AN: 34846

South Asian (SAS) AF: 0.360 AC: 26361 AN: 73244

European-Finnish (FIN) AF: 0.421 AC: 20287 AN: 48214

Middle Eastern (MID) AF: 0.342 AC: 1862 AN: 5444

European-Non Finnish (NFE) AF: 0.415 AC: 414988 AN: 999480

Other (OTH) AF: 0.370 AC: 20181 AN: 54474

GnomAD4 genome AF: 0.346 AC: 47710 AN: 137938 Hom.: 8368 Cov.: 30 AF XY: 0.344 AC XY: 23085 AN XY: 67074

African (AFR) AF: 0.199 AC: 6951 AN: 34902

American (AMR) AF: 0.329 AC: 4506 AN: 13702

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1398 AN: 3316

East Asian (EAS) AF: 0.154 AC: 705 AN: 4586

South Asian (SAS) AF: 0.354 AC: 1595 AN: 4500

European-Finnish (FIN) AF: 0.435 AC: 4149 AN: 9538

Middle Eastern (MID) AF: 0.354 AC: 95 AN: 268

European-Non Finnish (NFE) AF: 0.422 AC: 27173 AN: 64330

Other (OTH) AF: 0.359 AC: 684 AN: 1906

Alfa AF: 0.591 Hom.: 43207

Bravo AF: 0.305

Asia WGS AF: 0.218 AC: 742 AN: 3392

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 25, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 14, 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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

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. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.47
DANN	Benign	0.65
PhyloP100		0.60
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.030
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: rs6449209; hg19: chr4-15982166; COSMIC: COSV71699138; COSMIC: COSV71699138;