4-16013299-G-A

Variant names:

• chr4-16013299-G-A
• rs137853006
• NM_006017.3:c.1117C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_006017.3(PROM1):​c.1117C>T​(p.Arg373Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005881537: Functional study shows that this variant affects PROM1 function (PS3, PMID:18654668)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PROM1 NM_006017.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 0.303
• Publications: 67 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: Labcorp Genetics (formerly Invitae), G2P
• PROM1-related recessive retinopathy

  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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005881537: Functional study shows that this variant affects PROM1 function (PS3, PMID: 18654668).; SCV005904008: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18654668).; SCV000568218: Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein mislocalization (PMID: 18654668);; SCV001232460: Experimental studies have shown that this missense change affects PROM1 function (PMID: 18654668).; SCV001250320: PS3:Supporting; SCV001950331: Based on this evidence we have classified this variant as Pathogenic. PS3, PP1-S.; SCV005416205: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 4-16013299-G-A is Pathogenic according to our data. Variant chr4-16013299-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1117C>T	p.Arg373Cys	missense	Exon 11 of 28	NP_006008.1	O43490-1
	PROM1	NM_001145847.2		c.1090C>T	p.Arg364Cys	missense	Exon 10 of 27	NP_001139319.1	O43490-2
	PROM1	NM_001145848.2		c.1090C>T	p.Arg364Cys	missense	Exon 10 of 27	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.1117C>T	p.Arg373Cys	missense	Exon 11 of 28	ENSP00000415481.2	O43490-1
	PROM1	ENST00000505450.5	TSL:1	c.1090C>T	p.Arg364Cys	missense	Exon 10 of 27	ENSP00000426090.1	O43490-2
	PROM1	ENST00000508167.5	TSL:1	c.1090C>T	p.Arg364Cys	missense	Exon 10 of 27	ENSP00000427346.1	O43490-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249148 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456900 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725068

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107548

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000414 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
4	-	-	Retinal dystrophy (4)
3	-	-	Retinal macular dystrophy type 2 (3)
2	-	-	Cone-rod dystrophy 12 (2)
2	-	-	Stargardt disease 4;C2675210:Cone-rod dystrophy 12;C2677516:Retinitis pigmentosa 41;C4749334:Retinal macular dystrophy type 2 (2)
1	-	-	Macular dystrophy (1)
1	-	-	Retinal disorder (1)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Stargardt disease (1)
1	-	-	Stargardt disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.30
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.94	P
Vest4		0.66
MutPred		0.82		Loss of MoRF binding (P = 0.0109)
MVP		0.56
MPC		0.018
ClinPred		0.18	T
GERP RS		-0.57
Varity_R		0.22
gMVP		0.33
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.080		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: rs137853006; hg19: chr4-16014922; COSMIC: COSV101477144;