GeneBe

chr4-16038994-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

2

Clinical Significance

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

Conservation

PhyloP100: -0.432
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PROM1NM_006017.3 linkc.228G>A p.Leu76Leu synonymous_variant Exon 3 of 28 ENST00000447510.7 NP_006008.1 O43490-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PROM1ENST00000447510.7 linkc.228G>A p.Leu76Leu synonymous_variant Exon 3 of 28 1 NM_006017.3 ENSP00000415481.2 O43490-1

Frequencies

GnomAD3 genomes
AF:
0.0350
AC:
5308
AN:
151868
Hom.:
146
Cov.:
32
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
GnomAD3 exomes
AF:
0.0211
AC:
3360
AN:
159262
Hom.:
47
AF XY:
0.0217
AC XY:
1885
AN XY:
86934
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 SAS exome
AF:
0.0315
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.:
29
AF XY:
0.0229
AC XY:
15101
AN XY:
659890
show subpopulations
Gnomad4 AFR exome
AF:
0.0592
Gnomad4 AMR exome
AF:
0.0161
Gnomad4 ASJ exome
AF:
0.0296
Gnomad4 EAS exome
AF:
0.00227
Gnomad4 SAS exome
AF:
0.0326
Gnomad4 FIN exome
AF:
0.00700
Gnomad4 NFE exome
AF:
0.0222
Gnomad4 OTH exome
AF:
0.0291
GnomAD4 genome
AF:
0.0350
AC:
5318
AN:
151984
Hom.:
148
Cov.:
32
AF XY:
0.0342
AC XY:
2540
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.0694
Gnomad4 AMR
AF:
0.0269
Gnomad4 ASJ
AF:
0.0331
Gnomad4 EAS
AF:
0.00270
Gnomad4 SAS
AF:
0.0372
Gnomad4 FIN
AF:
0.00627
Gnomad4 NFE
AF:
0.0230
Gnomad4 OTH
AF:
0.0280
Alfa
AF:
0.0290
Hom.:
37
Bravo
AF:
0.0386
Asia WGS
AF:
0.0310
AC:
107
AN:
3446

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 15, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 14, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Stargardt disease 4 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinal macular dystrophy type 2 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinal dystrophy Benign:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cone-rod dystrophy 12 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.87
CADD
Benign
0.40
DANN
Benign
0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs76963591; hg19: chr4-16040617; COSMIC: COSV71699385; COSMIC: COSV71699385; API