Genetic Variant RPGRIP1:p.Lys435Gln (chr14-21317847-A-C) – 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.1303A>C(p.Lys435Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.69

Publications

0 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: Labcorp Genetics (formerly Invitae), G2P
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=0.11427748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 11 of 25	ENST00000400017.7	NP_065099.3	Q96KN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7 link	c.1303A>C	p.Lys435Gln	missense_variant	Exon 11 of 25	1	NM_020366.4	ENSP00000382895.2		Q96KN7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451016

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720236

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

43332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25782

East Asian (EAS)

AF:

0.00

AC:

AN:

39508

South Asian (SAS)

AF:

0.00

AC:

AN:

84032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106300

Other (OTH)

AF:

0.00

AC:

AN:

59978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.032

T;T;T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.7

.;.;L;.;.

PhyloP100

1.7

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;D

Polyphen

0.087, 0.035

.;.;B;B;.

Vest4

0.23

MutPred

0.15

.;.;Loss of ubiquitination at K435 (P = 0.0023);.;.;

MVP

0.76

MPC

0.073

ClinPred

0.068

GERP RS

0.71

PromoterAI

-0.0081

Neutral

(source)

Varity_R

0.083

gMVP

0.21

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over