NM_020366.4:c.525A>G

Variant names:

• chr14-21302522-A-G
• rs17792599
• NM_020366.4:c.525A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 99826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.525A>G	p.Pro175Pro	synonymous_variant	Exon 5 of 25	ENST00000400017.7	NP_065099.3

Ensembl

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

GnomAD2 exomes AF: 0.157 AC: 35780 AN: 227846 AF XY: 0.158

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 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

African (AFR) AF: 0.128 AC: 4228 AN: 33056

American (AMR) AF: 0.118 AC: 5024 AN: 42580

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10011 AN: 25314

East Asian (EAS) AF: 0.0866 AC: 3386 AN: 39118

South Asian (SAS) AF: 0.119 AC: 9644 AN: 80970

European-Finnish (FIN) AF: 0.106 AC: 5528 AN: 51920

Middle Eastern (MID) AF: 0.252 AC: 1433 AN: 5682

European-Non Finnish (NFE) AF: 0.180 AC: 196758 AN: 1094082

Other (OTH) AF: 0.190 AC: 11199 AN: 59056

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

African (AFR) AF: 0.127 AC: 5289 AN: 41532

American (AMR) AF: 0.162 AC: 2470 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1321 AN: 3470

East Asian (EAS) AF: 0.0868 AC: 449 AN: 5174

South Asian (SAS) AF: 0.113 AC: 547 AN: 4822

European-Finnish (FIN) AF: 0.109 AC: 1155 AN: 10602

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12254 AN: 68016

Other (OTH) AF: 0.208 AC: 441 AN: 2116

Alfa AF: 0.183 Hom.: 6469

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 12, 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 12, 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	-0.87
CADD	Benign	2.5
DANN	Benign	0.34
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17792599; hg19: chr14-21770681; COSMIC: COSV52850162;