rs147586703

chr14-21321995-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_020366.4(RPGRIP1):c.1753C>T(p.Pro585Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,612,198 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (3 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.746

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0085558).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (227/152300) while in subpopulation NFE AF= 0.00222 (151/68028). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.1753C>T	p.Pro585Ser	missense_variant	14/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.1753C>T	p.Pro585Ser	missense_variant	14/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00168 AC: 414 AN: 247034 Hom.: 1 AF XY: 0.00175 AC XY: 235 AN XY: 134096

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00331

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00269 AC: 3933 AN: 1459898 Hom.: 3 Cov.: 31 AF XY: 0.00261 AC XY: 1896 AN XY: 726214

Gnomad4 AFR exome AF: 0.000450

Gnomad4 AMR exome AF: 0.000587

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00339

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74464

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00143

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.00156 AC: 189

EpiCase AF: 0.00218

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Leber congenital amaurosis 6 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 14, 2022

Variant summary: RPGRIP1 c.1753C>T (p.Pro585Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 248042 control chromosomes, predominantly at a frequency of 0.0028 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGRIP1 causing Leber Congenital Amaurosis phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1753C>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis, Primary Open-Angle Glaucoma or Retinitis Pigmentosa (Wiszniewski_2010, Fernndez-Martnez_2011, Ge_2015, Wang_2017). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Cone-rod dystrophy 13 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.025	T;T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.0086	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.58	D;D;D;D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N;D;N;N
REVEL	Benign	0.22
Sift	Benign	0.12	T;T;T;T
Sift4G	Uncertain	0.0080	D;T;D;T
Polyphen		0.51, 1.0, 0.041	.;P;D;B
Vest4		0.48
MVP		0.79
MPC		0.15
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147586703; hg19: chr14-21790154;