rs17792599

Positions:

• chr14-21302522-A-G

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.525A>G​(p.Pro175Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,583,980 control chromosomes in the GnomAD database, including 25,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2146 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23007 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.77

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-21302522-A-G is Benign according to our data. Variant chr14-21302522-A-G is described in ClinVar as [Benign]. Clinvar id is 99826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21302522-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.525A>G	p.Pro175Pro	synonymous_variant	5/25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.525A>G	p.Pro175Pro	synonymous_variant	5/25	1	NM_020366.4	ENSP00000382895.2
RPGRIP1	ENST00000557771.5	c.525A>G	p.Pro175Pro	synonymous_variant	4/24	5		ENSP00000451219.1
RPGRIP1	ENST00000556336.5	c.525A>G	p.Pro175Pro	synonymous_variant	4/21	5		ENSP00000450445.1
RPGRIP1	ENST00000554750.1	n.124A>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24213 AN: 152084 Hom.: 2146 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.0862

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.157 AC: 35780 AN: 227846 Hom.: 3267 AF XY: 0.158 AC XY: 19435 AN XY: 122916

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.0941

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.173 AC: 247211 AN: 1431778 Hom.: 23007 Cov.: 30 AF XY: 0.172 AC XY: 122457 AN XY: 710066

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.0866

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.159 AC: 24214 AN: 152202 Hom.: 2146 Cov.: 33 AF XY: 0.154 AC XY: 11441 AN XY: 74416

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.381

Gnomad4 EAS AF: 0.0868

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.208

Alfa AF: 0.187 Hom.: 4931

Bravo AF: 0.165

Asia WGS AF: 0.0970 AC: 340 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cone-rod dystrophy 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.87
CADD	Benign	2.5
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17792599; hg19: chr14-21770681; COSMIC: COSV52850162;