chr4-16025218-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006017.3(PROM1):c.604C>G(p.Arg202Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,824 control chromosomes in the GnomAD database, including 2 homozygotes. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

PROM1
NM_006017.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:10

Conservation

PhyloP100: 1.44

Publications

5 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.604C>G	p.Arg202Gly	missense	Exon 6 of 28	NP_006008.1	O43490-1
PROM1	NM_001145847.2		c.577C>G	p.Arg193Gly	missense	Exon 5 of 27	NP_001139319.1	O43490-2
PROM1	NM_001145848.2		c.577C>G	p.Arg193Gly	missense	Exon 5 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.604C>G	p.Arg202Gly	missense	Exon 6 of 28	ENSP00000415481.2	O43490-1
PROM1	ENST00000505450.5	TSL:1	c.577C>G	p.Arg193Gly	missense	Exon 5 of 27	ENSP00000426090.1	O43490-2
PROM1	ENST00000508167.5	TSL:1	c.577C>G	p.Arg193Gly	missense	Exon 5 of 27	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000237

AC:

AN:

249174

AF XY:

0.000259

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000811

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1461504

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33476

American (AMR)

AF:

0.000738

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000162

AC:

180

AN:

1111714

Other (OTH)

AF:

0.000712

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000263

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41566

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000191

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000366

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive retinitis pigmentosa (1)

Retinal dystrophy (1)

Retinal macular dystrophy type 2 (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa 41 (1)

Stargardt disease 4 (1)

Stargardt disease 4;C2675210:Cone-rod dystrophy 12;C2677516:Retinitis pigmentosa 41;C4749334:Retinal macular dystrophy type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

PhyloP100

1.4

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.22

Sift

Uncertain

0.010

Sift4G

Uncertain

0.021

Polyphen

0.99

Vest4

0.82

MVP

0.76

MPC

0.028

ClinPred

0.099

GERP RS

0.018

Varity_R

0.31

gMVP

0.30

Mutation Taster

=0/100

disease causing

(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