dbSNP rs3748361: RPGRIP1:p.Glu1033Lys (chr14-21328625-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020366.4(RPGRIP1):c.3097G>A(p.Glu1033Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1033Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 missense, splice_region

Scores

Splicing: ADA: 0.00007319

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.30

Publications

36 publications found

Variant links:

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

cone-rod dystrophy 13
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPGRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17433569).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	NM_020366.4	MANE Select	c.3097G>A	p.Glu1033Lys	missense splice_region	Exon 19 of 25	NP_065099.3
RPGRIP1	NM_001377948.1		c.2023G>A	p.Glu675Lys	missense splice_region	Exon 9 of 15	NP_001364877.1
RPGRIP1	NM_001377949.1		c.1183G>A	p.Glu395Lys	missense splice_region	Exon 7 of 13	NP_001364878.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.3097G>A	p.Glu1033Lys	missense splice_region	Exon 19 of 25	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000555587.5	TSL:1	c.1522G>A	p.Glu508Lys	missense splice_region	Exon 7 of 13	ENSP00000451262.1	G3V3I7
RPGRIP1	ENST00000382933.8	TSL:1	c.1075G>A	p.Glu359Lys	missense splice_region	Exon 6 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453690

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104756

Other (OTH)

AF:

0.00

AC:

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.015

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.81

M_CAP

Benign

0.040

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.69

PhyloP100

1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.71

REVEL

Benign

0.088

Sift

Benign

0.31

Sift4G

Uncertain

0.026

Polyphen

0.0050

Vest4

0.24

MutPred

0.34

Gain of ubiquitination at E1033 (P = 0.0082)

MVP

0.69

MPC

0.077

ClinPred

0.074

GERP RS

1.8

PromoterAI

0.028

Neutral

(source)

Varity_R

0.065

gMVP

0.31

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over