4-16075214-A-T

Variant names:

• chr4-16075214-A-T
• rs10022537
• NM_006017.3:c.220+473T>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.220+473T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 152,054 control chromosomes in the GnomAD database, including 39,552 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 0.71 (39552 hom., cov: 32)
• Consequence: PROM1 NM_006017.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.483
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROM1	NM_006017.3	c.220+473T>A		intron_variant	Intron 2 of 27	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.220+473T>A		intron_variant	Intron 2 of 27	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107611 AN: 151936 Hom.: 39530 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.722

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

GnomAD4 genome AF: 0.708 AC: 107663 AN: 152054 Hom.: 39552 Cov.: 32 AF XY: 0.707 AC XY: 52532 AN XY: 74312

African (AFR) AF: 0.498 AC: 20608 AN: 41418

American (AMR) AF: 0.719 AC: 10997 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2752 AN: 3472

East Asian (EAS) AF: 0.710 AC: 3666 AN: 5164

South Asian (SAS) AF: 0.763 AC: 3677 AN: 4822

European-Finnish (FIN) AF: 0.761 AC: 8044 AN: 10566

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55416 AN: 67992

Other (OTH) AF: 0.726 AC: 1536 AN: 2116

Alfa AF: 0.752 Hom.: 5516

Bravo AF: 0.696

Asia WGS AF: 0.737 AC: 2563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.68
DANN	Benign	0.46
PhyloP100		-0.48
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: rs10022537; hg19: chr4-16076837;