Genetic Variant PROM1:p.Ala262Ala (chr4-16018539-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.786G>A(p.Ala262Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,602,056 control chromosomes in the GnomAD database, including 12,324 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 0.10 ( 1043 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11281 hom. )

Consequence

PROM1
NM_006017.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00004434

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.04

Publications

31 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):

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

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=-0.94).

BP6

Variant 4-16018539-C-T is Benign according to our data. Variant chr4-16018539-C-T is described in ClinVar as Benign. ClinVar VariationId is 259907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 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
PROM1	NM_006017.3	MANE Select	c.786G>A	p.Ala262Ala	splice_region synonymous	Exon 9 of 28	NP_006008.1
PROM1	NM_001145847.2		c.759G>A	p.Ala253Ala	splice_region synonymous	Exon 8 of 27	NP_001139319.1
PROM1	NM_001145848.2		c.759G>A	p.Ala253Ala	splice_region synonymous	Exon 8 of 27	NP_001139320.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PROM1	ENST00000447510.7	TSL:1 MANE Select	c.786G>A	p.Ala262Ala	splice_region synonymous	Exon 9 of 28	ENSP00000415481.2
PROM1	ENST00000505450.5	TSL:1	c.759G>A	p.Ala253Ala	splice_region synonymous	Exon 8 of 27	ENSP00000426090.1
PROM1	ENST00000508167.5	TSL:1	c.759G>A	p.Ala253Ala	splice_region synonymous	Exon 8 of 27	ENSP00000427346.1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15768

AN:

152054

Hom.:

1039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0449

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.143

AC:

33306

AN:

232980

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.0436

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.117

AC:

170121

AN:

1449884

Hom.:

11281

Cov.:

AF XY:

0.120

AC XY:

86113

AN XY:

720192

show subpopulations

African (AFR)

AF:

0.0407

AC:

1354

AN:

33306

American (AMR)

AF:

0.194

AC:

8372

AN:

43054

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3376

AN:

25900

East Asian (EAS)

AF:

0.274

AC:

10795

AN:

39340

South Asian (SAS)

AF:

0.192

AC:

16199

AN:

84548

European-Finnish (FIN)

AF:

0.117

AC:

6214

AN:

52968

Middle Eastern (MID)

AF:

0.142

AC:

612

AN:

4312

European-Non Finnish (NFE)

AF:

0.105

AC:

116006

AN:

1106528

Other (OTH)

AF:

0.120

AC:

7193

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

7138

14276

21414

28552

35690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4324

8648

12972

17296

21620

<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:

0.104

AC:

15793

AN:

152172

Hom.:

1043

Cov.:

AF XY:

0.106

AC XY:

7854

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0449

AC:

1863

AN:

41510

American (AMR)

AF:

0.134

AC:

2053

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

464

AN:

3470

East Asian (EAS)

AF:

0.253

AC:

1310

AN:

5172

South Asian (SAS)

AF:

0.197

AC:

947

AN:

4816

European-Finnish (FIN)

AF:

0.116

AC:

1232

AN:

10590

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7593

AN:

68008

Other (OTH)

AF:

0.114

AC:

241

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

705

1409

2114

2818

3523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.115

Hom.:

5294

Bravo

AF:

0.103

Asia WGS

AF:

0.194

AC:

676

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

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

-0.94

CADD

Benign

0.32

(source)

DANN

Benign

0.43

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.016

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