rs9322965

Variant names:

• chr14-21324652-G-A
• rs9322965
• NM_020366.4:c.1797G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-21324652-G-A
• chr14-21324652-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020366.4(RPGRIP1):​c.1797G>A​(p.Pro599Pro) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.372

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: 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: Synonymous conserved (PhyloP=-0.372 with no splicing effect.
• BA1: 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 rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.1797G>A	p.Pro599Pro	synonymous_variant	Exon 15 of 25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.1797G>A	p.Pro599Pro	synonymous_variant	Exon 15 of 25	1	NM_020366.4	ENSP00000382895.2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33490 AN: 152024 Hom.: 3899 Cov.: 32

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

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

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 AF: 0.220 AC: 33522 AN: 152142 Hom.: 3898 Cov.: 32 AF XY: 0.219 AC XY: 16282 AN XY: 74386

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 13 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

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

Other links and lift over

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