rs7157052

Positions:

• chr14-21325077-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.2215+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,599,062 control chromosomes in the GnomAD database, including 38,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3235 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35736 hom.)
• Consequence: RPGRIP1 NM_020366.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.875

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-21325077-G-A is Benign according to our data. Variant chr14-21325077-G-A is described in ClinVar as [Benign]. Clinvar id is 261227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21325077-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.2215+7G>A		splice_region_variant, intron_variant		ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.2215+7G>A		splice_region_variant, intron_variant		1	NM_020366.4	ENSP00000382895	P2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29940 AN: 152070 Hom.: 3235 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.191 AC: 46320 AN: 242254 Hom.: 5182 AF XY: 0.197 AC XY: 25882 AN XY: 131422

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0948

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.00431

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.217 AC: 313602 AN: 1446874 Hom.: 35736 Cov.: 31 AF XY: 0.217 AC XY: 155901 AN XY: 717886

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.00332

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.197 AC: 29959 AN: 152188 Hom.: 3235 Cov.: 32 AF XY: 0.194 AC XY: 14450 AN XY: 74420

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.00540

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.180

Alfa AF: 0.216 Hom.: 6225

Bravo AF: 0.185

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 13, 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 13, 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	-0.84
CADD	Benign	8.3
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		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: rs7157052; hg19: chr14-21793236; COSMIC: COSV52849042; COSMIC: COSV52849042;