4-15984361-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006017.3(PROM1):c.2281-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,556,772 control chromosomes in the GnomAD database, including 47,813 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 0.20 ( 3874 hom., cov: 32)

Exomes 𝑓: 0.25 ( 43939 hom. )

Consequence

PROM1
NM_006017.3 splice_region, intron

Scores

Splicing: ADA: 0.2205

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.622

Publications

15 publications found

Variant links:

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

PROM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 4-15984361-G-C is Benign according to our data. Variant chr4-15984361-G-C is described in ClinVar as Benign. ClinVar VariationId is 95330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PROM1	NM_006017.3	MANE Select	c.2281-6C>G	splice_region intron	N/A	NP_006008.1	O43490-1
PROM1	NM_001145847.2		c.2254-6C>G	splice_region intron	N/A	NP_001139319.1	O43490-2
PROM1	NM_001145848.2		c.2254-6C>G	splice_region intron	N/A	NP_001139320.1	O43490-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PROM1	ENST00000447510.7	TSL:1 MANE Select	c.2281-6C>G	splice_region intron	N/A	ENSP00000415481.2	O43490-1
PROM1	ENST00000505450.5	TSL:1	c.2254-6C>G	splice_region intron	N/A	ENSP00000426090.1	O43490-2
PROM1	ENST00000508167.5	TSL:1	c.2254-6C>G	splice_region intron	N/A	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31162

AN:

151984

Hom.:

3879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0691

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.263

Gnomad OTH

AF:

0.234

GnomAD2 exomes

AF:

0.242

AC:

50071

AN:

207112

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.0611

Gnomad AMR exome

AF:

0.329

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.277

GnomAD4 exome

AF:

0.246

AC:

345650

AN:

1404670

Hom.:

43939

Cov.:

AF XY:

0.246

AC XY:

171559

AN XY:

696292

show subpopulations

African (AFR)

AF:

0.0636

AC:

2023

AN:

31808

American (AMR)

AF:

0.319

AC:

12195

AN:

38242

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

6121

AN:

24600

East Asian (EAS)

AF:

0.0926

AC:

3558

AN:

38436

South Asian (SAS)

AF:

0.218

AC:

16828

AN:

77244

European-Finnish (FIN)

AF:

0.236

AC:

12257

AN:

51854

Middle Eastern (MID)

AF:

0.294

AC:

1635

AN:

5554

European-Non Finnish (NFE)

AF:

0.257

AC:

276827

AN:

1078788

Other (OTH)

AF:

0.244

AC:

14206

AN:

58144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

10668

21335

32003

42670

53338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9210

18420

27630

36840

46050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.205

AC:

31145

AN:

152102

Hom.:

3874

Cov.:

AF XY:

0.208

AC XY:

15481

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0690

AC:

2864

AN:

41522

American (AMR)

AF:

0.315

AC:

4812

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

801

AN:

3470

East Asian (EAS)

AF:

0.118

AC:

612

AN:

5176

South Asian (SAS)

AF:

0.208

AC:

1002

AN:

4816

European-Finnish (FIN)

AF:

0.236

AC:

2491

AN:

10574

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.263

AC:

17846

AN:

67972

Other (OTH)

AF:

0.230

AC:

485

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1218

2435

3653

4870

6088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

336

672

1008

1344

1680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.220

Hom.:

1274

Bravo

AF:

0.200

Asia WGS

AF:

0.178

AC:

617

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cone-rod dystrophy 12 (2)

not specified (2)

Retinal macular dystrophy type 2 (2)

Stargardt disease 4 (2)

Retinitis pigmentosa (1)

Retinitis pigmentosa 41 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.0

(source)

DANN

Benign

0.50

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over