chr14-21288061-G-A

Position:

• chr14-21288061-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020366.4(RPGRIP1):​c.85G>A​(p.Gly29Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RPGRIP1 NM_020366.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.85G>A	p.Gly29Ser	missense_variant, splice_region_variant	2/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.85G>A	p.Gly29Ser	missense_variant, splice_region_variant	2/25	1	NM_020366.4	P2
RPGRIP1	ENST00000557771.5	c.85G>A	p.Gly29Ser	missense_variant, splice_region_variant	1/24	5		A2
RPGRIP1	ENST00000556336.5	c.85G>A	p.Gly29Ser	missense_variant, splice_region_variant	1/21	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1005094). This variant has not been reported in the literature in individuals affected with RPGRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 29 of the RPGRIP1 protein (p.Gly29Ser). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.9	.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.50
MutPred		0.21		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.79
MPC		0.17
ClinPred		0.60	D
GERP RS		3.2
Varity_R		0.076
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763401090; hg19: chr14-21756220;