4-15991208-C-T

Variant names:

• chr4-15991208-C-T
• rs4698436
• NM_006017.3:c.1983+14G>A

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.1983+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,595,646 control chromosomes in the GnomAD database, including 1,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (319 hom., cov: 32)
  • Exomes 𝑓: 0.025 (1441 hom.)
• Consequence: PROM1 NM_006017.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0260

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 (BayesDel_noAF=-0.83).
• BP6: Variant 4-15991208-C-T is Benign according to our data. Variant chr4-15991208-C-T is described in ClinVar as [Benign]. Clinvar id is 259905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15991208-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROM1	NM_006017.3	c.1983+14G>A		intron_variant	Intron 18 of 27	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.1983+14G>A		intron_variant	Intron 18 of 27	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6889 AN: 152140 Hom.: 318 Cov.: 32

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0486 AC: 11577 AN: 238268 Hom.: 624 AF XY: 0.0452 AC XY: 5856 AN XY: 129532

Gnomad AFR exome AF: 0.0747

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.0696

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0251 AC: 36170 AN: 1443388 Hom.: 1441 Cov.: 29 AF XY: 0.0256 AC XY: 18377 AN XY: 718176

Gnomad4 AFR exome AF: 0.0768

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.0669

Gnomad4 FIN exome AF: 0.0300

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0453 AC: 6901 AN: 152258 Hom.: 319 Cov.: 32 AF XY: 0.0475 AC XY: 3539 AN XY: 74442

Gnomad4 AFR AF: 0.0772

Gnomad4 AMR AF: 0.0624

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.0910

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0365 Hom.: 43

Bravo AF: 0.0505

Asia WGS AF: 0.118 AC: 409 AN: 3478

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

- -

Jul 05, 2018

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	-0.83
CADD	Benign	5.0
DANN	Benign	0.56

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: rs4698436; hg19: chr4-15992831;