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GeneBe

rs9322965

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020366.4(RPGRIP1):​c.1797G>A​(p.Pro599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,613,316 control chromosomes in the GnomAD database, including 44,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3898 hom., cov: 32)
Exomes 𝑓: 0.23 ( 40242 hom. )

Consequence

RPGRIP1
NM_020366.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.372
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-21324652-G-A is Benign according to our data. Variant chr14-21324652-G-A is described in ClinVar as [Benign]. Clinvar id is 99812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21324652-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.372 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPGRIP1NM_020366.4 linkuse as main transcriptc.1797G>A p.Pro599= synonymous_variant 15/25 ENST00000400017.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPGRIP1ENST00000400017.7 linkuse as main transcriptc.1797G>A p.Pro599= synonymous_variant 15/251 NM_020366.4 P2Q96KN7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.220
AC:
33490
AN:
152024
Hom.:
3899
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.228
Gnomad AMI
AF:
0.231
Gnomad AMR
AF:
0.146
Gnomad ASJ
AF:
0.184
Gnomad EAS
AF:
0.0187
Gnomad SAS
AF:
0.265
Gnomad FIN
AF:
0.256
Gnomad MID
AF:
0.271
Gnomad NFE
AF:
0.241
Gnomad OTH
AF:
0.205
GnomAD3 exomes
AF:
0.207
AC:
51517
AN:
249100
Hom.:
6177
AF XY:
0.214
AC XY:
28949
AN XY:
135174
show subpopulations
Gnomad AFR exome
AF:
0.226
Gnomad AMR exome
AF:
0.105
Gnomad ASJ exome
AF:
0.185
Gnomad EAS exome
AF:
0.0159
Gnomad SAS exome
AF:
0.275
Gnomad FIN exome
AF:
0.259
Gnomad NFE exome
AF:
0.239
Gnomad OTH exome
AF:
0.217
GnomAD4 exome
AF:
0.230
AC:
335615
AN:
1461174
Hom.:
40242
Cov.:
34
AF XY:
0.231
AC XY:
167974
AN XY:
726906
show subpopulations
Gnomad4 AFR exome
AF:
0.225
Gnomad4 AMR exome
AF:
0.113
Gnomad4 ASJ exome
AF:
0.179
Gnomad4 EAS exome
AF:
0.0195
Gnomad4 SAS exome
AF:
0.273
Gnomad4 FIN exome
AF:
0.262
Gnomad4 NFE exome
AF:
0.239
Gnomad4 OTH exome
AF:
0.226
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.220
AC:
33522
AN:
152142
Hom.:
3898
Cov.:
32
AF XY:
0.219
AC XY:
16282
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.228
Gnomad4 AMR
AF:
0.146
Gnomad4 ASJ
AF:
0.184
Gnomad4 EAS
AF:
0.0187
Gnomad4 SAS
AF:
0.266
Gnomad4 FIN
AF:
0.256
Gnomad4 NFE
AF:
0.241
Gnomad4 OTH
AF:
0.208
Alfa
AF:
0.231
Hom.:
7028
Bravo
AF:
0.209
Asia WGS
AF:
0.176
AC:
614
AN:
3478
EpiCase
AF:
0.232
EpiControl
AF:
0.227

ClinVar

Significance: Benign
Submissions summary: Benign:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 21, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Cone-rod dystrophy 13 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Leber congenital amaurosis 6 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Other:1
not provided, no classification providedliterature onlyRetina International-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
6.9
DANN
Benign
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs9322965; hg19: chr14-21792811; COSMIC: COSV99251668; COSMIC: COSV99251668; API