4-16016701-C-T

Variant names:

• chr4-16016701-C-T
• rs2531154
• NM_006017.3:c.1003-461G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006017.3(PROM1):​c.1003-461G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 152,184 control chromosomes in the GnomAD database, including 60,917 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60917 hom., cov: 32)
• Consequence: PROM1 NM_006017.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.454
• Publications: 7 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):

• PROM1-related dominant retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinal macular dystrophy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• PROM1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 41

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006017.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	NM_006017.3	MANE Select	c.1003-461G>A		intron	N/A	NP_006008.1	O43490-1
	PROM1	NM_001145847.2		c.976-461G>A		intron	N/A	NP_001139319.1	O43490-2
	PROM1	NM_001145848.2		c.976-461G>A		intron	N/A	NP_001139320.1	O43490-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROM1	ENST00000447510.7	TSL:1 MANE Select	c.1003-461G>A		intron	N/A	ENSP00000415481.2	O43490-1
	PROM1	ENST00000505450.5	TSL:1	c.976-461G>A		intron	N/A	ENSP00000426090.1	O43490-2
	PROM1	ENST00000508167.5	TSL:1	c.976-461G>A		intron	N/A	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes AF: 0.892 AC: 135672 AN: 152066 Hom.: 60856 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.900

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.892 AC: 135792 AN: 152184 Hom.: 60917 Cov.: 32 AF XY: 0.887 AC XY: 65956 AN XY: 74394

African (AFR) AF: 0.864 AC: 35866 AN: 41506

American (AMR) AF: 0.808 AC: 12349 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 3279 AN: 3470

East Asian (EAS) AF: 0.708 AC: 3660 AN: 5166

South Asian (SAS) AF: 0.845 AC: 4075 AN: 4820

European-Finnish (FIN) AF: 0.932 AC: 9873 AN: 10588

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63670 AN: 68024

Other (OTH) AF: 0.900 AC: 1903 AN: 2114

Alfa AF: 0.916 Hom.: 42443

Bravo AF: 0.884

Asia WGS AF: 0.753 AC: 2621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.3
DANN	Benign	0.46
PhyloP100		0.45
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: rs2531154; hg19: chr4-16018324;