rs34269395

Positions:

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

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006017.3(PROM1):​c.2374-4_2374-3insC variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.539

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 -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROM1	NM_006017.3	c.2374-4_2374-3insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000447510.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROM1	ENST00000447510.7	c.2374-4_2374-3insC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006017.3	P3

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

GnomAD3 exomes AF: 0.282 AC: 41237 AN: 146440 Hom.: 5795 AF XY: 0.278 AC XY: 21518 AN XY: 77404

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 SAS exome AF: 0.257

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

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.304

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.269

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

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.293

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular dystrophy, retinal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cone-Rod Dystrophy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs34269395; hg19: chr4-15982163;