rs10033086

Variant names:

• chr4-16075778-G-A
• rs10033086
• NM_006017.3:c.129C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PROM1	NM_006017.3	c.129C>T	p.Thr43Thr	synonymous_variant	Exon 2 of 28	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.129C>T	p.Thr43Thr	synonymous_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.0354 AC: 8813 AN: 248726 AF XY: 0.0316

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 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

African (AFR) AF: 0.248 AC: 8289 AN: 33464

American (AMR) AF: 0.0214 AC: 956 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 766 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00729 AC: 628 AN: 86184

European-Finnish (FIN) AF: 0.0449 AC: 2395 AN: 53390

Middle Eastern (MID) AF: 0.0421 AC: 243 AN: 5768

European-Non Finnish (NFE) AF: 0.0224 AC: 24900 AN: 1111788

Other (OTH) AF: 0.0360 AC: 2175 AN: 60364

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

African (AFR) AF: 0.235 AC: 9746 AN: 41446

American (AMR) AF: 0.0351 AC: 537 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.00956 AC: 46 AN: 4812

European-Finnish (FIN) AF: 0.0465 AC: 493 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1758 AN: 68000

Other (OTH) AF: 0.0649 AC: 137 AN: 2112

Alfa AF: 0.0375 Hom.: 565

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Feb 02, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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. -

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	-0.75
CADD	Benign	2.4
DANN	Benign	0.34
PhyloP100		-0.092
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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