rs2078622

Variant names:

• chr4-16035729-C-T
• rs2078622
• NM_006017.3:c.303+6G>A

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.303+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,956 control chromosomes in the GnomAD database, including 217,307 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 0.40 (14768 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202539 hom.)
• Consequence: PROM1 NM_006017.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001957
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.700
• Publications: 18 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=-0.73).
• BP6: Variant 4-16035729-C-T is Benign according to our data. Variant chr4-16035729-C-T is described in ClinVar as Benign. ClinVar VariationId is 259906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.546 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	NM_006017.3	MANE Select	c.303+6G>A		splice_region intron	N/A	NP_006008.1
	PROM1	NM_001145847.2		c.277-2220G>A		intron	N/A	NP_001139319.1
	PROM1	NM_001145848.2		c.277-2220G>A		intron	N/A	NP_001139320.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	ENST00000447510.7	TSL:1 MANE Select	c.303+6G>A		splice_region intron	N/A	ENSP00000415481.2
	PROM1	ENST00000505450.5	TSL:1	c.277-2220G>A		intron	N/A	ENSP00000426090.1
	PROM1	ENST00000508167.5	TSL:1	c.277-2220G>A		intron	N/A	ENSP00000427346.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60374 AN: 151998 Hom.: 14761 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.449 AC: 111659 AN: 248760 AF XY: 0.463

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.517 AC: 753858 AN: 1457840 Hom.: 202539 Cov.: 41 AF XY: 0.518 AC XY: 375526 AN XY: 725406

African (AFR) AF: 0.112 AC: 3745 AN: 33442

American (AMR) AF: 0.324 AC: 14456 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 13420 AN: 26110

East Asian (EAS) AF: 0.184 AC: 7312 AN: 39672

South Asian (SAS) AF: 0.464 AC: 39928 AN: 86098

European-Finnish (FIN) AF: 0.522 AC: 27794 AN: 53284

Middle Eastern (MID) AF: 0.520 AC: 2999 AN: 5764

European-Non Finnish (NFE) AF: 0.555 AC: 615113 AN: 1108540

Other (OTH) AF: 0.483 AC: 29091 AN: 60262

GnomAD4 genome AF: 0.397 AC: 60376 AN: 152116 Hom.: 14768 Cov.: 33 AF XY: 0.394 AC XY: 29328 AN XY: 74356

African (AFR) AF: 0.121 AC: 5044 AN: 41520

American (AMR) AF: 0.392 AC: 5983 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3466

East Asian (EAS) AF: 0.158 AC: 819 AN: 5176

South Asian (SAS) AF: 0.447 AC: 2156 AN: 4826

European-Finnish (FIN) AF: 0.516 AC: 5457 AN: 10572

Middle Eastern (MID) AF: 0.548 AC: 159 AN: 290

European-Non Finnish (NFE) AF: 0.551 AC: 37465 AN: 67976

Other (OTH) AF: 0.455 AC: 960 AN: 2108

Alfa AF: 0.492 Hom.: 61180

Bravo AF: 0.375

Asia WGS AF: 0.312 AC: 1085 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.559

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Cone-rod dystrophy 12 (2)
-	-	2	Retinal macular dystrophy type 2 (2)
-	-	2	Stargardt disease 4 (2)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 41 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.2
DANN	Benign	0.59
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.090		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: rs2078622; hg19: chr4-16037352; COSMIC: COSV71699244;