rs189108830

Positions:

• chr4-16075852-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006017.3(PROM1):​c.55T>G​(p.Ser19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,608 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (24 hom., cov: 32)
  • Exomes 𝑓: 0.010 (171 hom.)
• Consequence: PROM1 NM_006017.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028541088).
• BP6: Variant 4-16075852-A-C is Benign according to our data. Variant chr4-16075852-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 193330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROM1	NM_006017.3	c.55T>G	p.Ser19Ala	missense_variant	2/28	ENST00000447510.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROM1	ENST00000447510.7	c.55T>G	p.Ser19Ala	missense_variant	2/28	1	NM_006017.3	P3

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1403 AN: 152130 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0149 AC: 3699 AN: 248340 Hom.: 103 AF XY: 0.0130 AC XY: 1745 AN XY: 134712

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.0638

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00378

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.00901

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0104 AC: 15236 AN: 1461360 Hom.: 171 Cov.: 31 AF XY: 0.0100 AC XY: 7300 AN XY: 726918

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.0589

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00404

Gnomad4 FIN exome AF: 0.00877

Gnomad4 NFE exome AF: 0.00992

Gnomad4 OTH exome AF: 0.00803

GnomAD4 genome AF: 0.00921 AC: 1402 AN: 152248 Hom.: 24 Cov.: 32 AF XY: 0.00889 AC XY: 662 AN XY: 74448

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.0304

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00917 Hom.: 14

Bravo AF: 0.0115

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00225 AC: 9

ESP6500EA AF: 0.00899 AC: 75

ExAC AF: 0.0126 AC: 1528

EpiCase AF: 0.00823

EpiControl AF: 0.0102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Stargardt disease 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Cone-rod dystrophy 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.7
DANN	Benign	0.60
DEOGEN2	Benign	0.22	T;.;.;.;.;T;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.43	T;T;T;.;T;.;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;N;N;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;D
REVEL	Benign	0.017
Sift	Benign	0.15	T;T;T;T;T;T;T;D
Sift4G	Benign	0.15	T;T;T;T;T;T;.;.
Polyphen		0.23	B;B;B;B;B;B;.;.
Vest4		0.026
MPC		0.015
ClinPred		0.0037	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.39

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

Other links and lift over

dbSNP: rs189108830; hg19: chr4-16077475;