rs10033086

Positions:

• chr4-16075778-G-A
• chr4-16075778-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006017.3(PROM1):​c.129C>T​(p.Thr43Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,613,598 control chromosomes in the GnomAD database, including 2,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1237 hom., cov: 32)
  • Exomes 𝑓: 0.028 (1506 hom.)
• Consequence: PROM1 NM_006017.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0920

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 4-16075778-G-A is Benign according to our data. Variant chr4-16075778-G-A is described in ClinVar as [Benign]. Clinvar id is 259902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-16075778-G-A is described in Lovd as [Benign]. Variant chr4-16075778-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROM1	NM_006017.3	c.129C>T	p.Thr43Thr	synonymous_variant	2/28	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.129C>T	p.Thr43Thr	synonymous_variant	2/28	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.0843 AC: 12806 AN: 151986 Hom.: 1228 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00976

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0656

GnomAD3 exomes AF: 0.0354 AC: 8813 AN: 248726 Hom.: 525 AF XY: 0.0316 AC XY: 4271 AN XY: 134960

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0287

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00718

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0276 AC: 40354 AN: 1461494 Hom.: 1506 Cov.: 30 AF XY: 0.0268 AC XY: 19456 AN XY: 727016

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00729

Gnomad4 FIN exome AF: 0.0449

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0845 AC: 12852 AN: 152104 Hom.: 1237 Cov.: 32 AF XY: 0.0834 AC XY: 6199 AN XY: 74372

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00956

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0410 Hom.: 244

Bravo AF: 0.0890

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0207

EpiControl AF: 0.0229

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.4
DANN	Benign	0.34

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: rs10033086; hg19: chr4-16077401; COSMIC: COSV71699362; COSMIC: COSV71699362;