Genetic Variant PROM1:p.Leu76Leu (chr4-16038994-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006017.3(PROM1):c.228G>A(p.Leu76Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,490,096 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 148 hom., cov: 32)

Exomes 𝑓: 0.023 ( 441 hom. )

Consequence

PROM1
NM_006017.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.432

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 4-16038994-C-T is Benign according to our data. Variant chr4-16038994-C-T is described in ClinVar as Benign. ClinVar VariationId is 95331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.432 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0672 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	HGVSp	Effect	Exon Rank	Protein	UniProt
PROM1	NM_006017.3	MANE Select	c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 28	NP_006008.1	O43490-1
PROM1	NM_001145847.2		c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 27	NP_001139319.1	O43490-2
PROM1	NM_001145848.2		c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 27	NP_001139320.1	O43490-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROM1	ENST00000447510.7	TSL:1 MANE Select	c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 28	ENSP00000415481.2	O43490-1
PROM1	ENST00000505450.5	TSL:1	c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 27	ENSP00000426090.1	O43490-2
PROM1	ENST00000508167.5	TSL:1	c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 27	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5308

AN:

151868

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0693

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0270

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.00627

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0211

AC:

3360

AN:

159262

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.0567

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.00755

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0228

AC:

30467

AN:

1338112

Hom.:

441

Cov.:

AF XY:

0.0229

AC XY:

15101

AN XY:

659890

show subpopulations

African (AFR)

AF:

0.0592

AC:

1695

AN:

28654

American (AMR)

AF:

0.0161

AC:

469

AN:

29142

Ashkenazi Jewish (ASJ)

AF:

0.0296

AC:

671

AN:

22690

East Asian (EAS)

AF:

0.00227

AC:

AN:

34864

South Asian (SAS)

AF:

0.0326

AC:

2098

AN:

64264

European-Finnish (FIN)

AF:

0.00700

AC:

342

AN:

48844

Middle Eastern (MID)

AF:

0.0404

AC:

215

AN:

5320

European-Non Finnish (NFE)

AF:

0.0222

AC:

23304

AN:

1049608

Other (OTH)

AF:

0.0291

AC:

1594

AN:

54726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

1322

2644

3965

5287

6609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

978

1956

2934

3912

4890

<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:

0.0350

AC:

5318

AN:

151984

Hom.:

148

Cov.:

AF XY:

0.0342

AC XY:

2540

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0694

AC:

2875

AN:

41454

American (AMR)

AF:

0.0269

AC:

411

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.00270

AC:

AN:

5180

South Asian (SAS)

AF:

0.0372

AC:

179

AN:

4806

European-Finnish (FIN)

AF:

0.00627

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0230

AC:

1563

AN:

67966

Other (OTH)

AF:

0.0280

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

251

503

754

1006

1257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0290

Hom.:

Bravo

AF:

0.0386

Asia WGS

AF:

0.0310

AC:

107

AN:

3446

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Cone-rod dystrophy 12 (1)

Retinal dystrophy (1)

Retinal macular dystrophy type 2 (1)

Retinitis pigmentosa (1)

Stargardt disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.40

(source)

DANN

Benign

0.30

PhyloP100

-0.43

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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