NM_006017.3:c.1768-5C>T

Variant names:

• chr4-15992396-G-A
• rs55708318
• NM_006017.3:c.1768-5C>T

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.1768-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,606,490 control chromosomes in the GnomAD database, including 1,781 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (117 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1664 hom.)
• Consequence: PROM1 NM_006017.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001316
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.27
• Publications: 7 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):

• PROM1-related dominant retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinal macular dystrophy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• PROM1-related recessive retinopathy

  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=-0.91).
• BP6: Variant 4-15992396-G-A is Benign according to our data. Variant chr4-15992396-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 100578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 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.1768-5C>T		splice_region intron	N/A	NP_006008.1	O43490-1
	PROM1	NM_001145847.2		c.1741-5C>T		splice_region intron	N/A	NP_001139319.1	O43490-2
	PROM1	NM_001145848.2		c.1741-5C>T		splice_region intron	N/A	NP_001139320.1	O43490-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	ENST00000447510.7	TSL:1 MANE Select	c.1768-5C>T		splice_region intron	N/A	ENSP00000415481.2	O43490-1
	PROM1	ENST00000505450.5	TSL:1	c.1741-5C>T		splice_region intron	N/A	ENSP00000426090.1	O43490-2
	PROM1	ENST00000508167.5	TSL:1	c.1741-5C>T		splice_region intron	N/A	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5296 AN: 151776 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0526

Gnomad OTH AF: 0.0393

GnomAD2 exomes AF: 0.0356 AC: 8687 AN: 243794 AF XY: 0.0365

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000171

Gnomad FIN exome AF: 0.0427

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0449 AC: 65302 AN: 1454596 Hom.: 1664 Cov.: 31 AF XY: 0.0448 AC XY: 32380 AN XY: 723244

African (AFR) AF: 0.00848 AC: 279 AN: 32886

American (AMR) AF: 0.0251 AC: 1086 AN: 43210

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 767 AN: 25994

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39598

South Asian (SAS) AF: 0.0196 AC: 1664 AN: 84824

European-Finnish (FIN) AF: 0.0421 AC: 2246 AN: 53356

Middle Eastern (MID) AF: 0.0536 AC: 307 AN: 5726

European-Non Finnish (NFE) AF: 0.0509 AC: 56450 AN: 1108934

Other (OTH) AF: 0.0414 AC: 2489 AN: 60068

GnomAD4 genome AF: 0.0349 AC: 5294 AN: 151894 Hom.: 117 Cov.: 32 AF XY: 0.0345 AC XY: 2558 AN XY: 74230

African (AFR) AF: 0.00946 AC: 392 AN: 41446

American (AMR) AF: 0.0358 AC: 546 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4816

European-Finnish (FIN) AF: 0.0443 AC: 464 AN: 10476

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0526 AC: 3572 AN: 67942

Other (OTH) AF: 0.0389 AC: 82 AN: 2106

Alfa AF: 0.0463 Hom.: 306

Bravo AF: 0.0317

EpiCase AF: 0.0515

EpiControl AF: 0.0559

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.48
DANN	Benign	0.32
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.14		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: rs55708318; hg19: chr4-15994019;