rs17103671

Positions:

• chr14-21343037-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.3341A>G​(p.Asp1114Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,611,002 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (124 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (141 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001004
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: -1.98

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 -18 ACMG points.

• PM1: In a region_of_interest Interaction with RPGR (size 190) in uniprot entity RPGR1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_020366.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010194093).
• BP6: Variant 14-21343037-A-G is Benign according to our data. Variant chr14-21343037-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 4988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21343037-A-G is described in Lovd as [Benign]. Variant chr14-21343037-A-G is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.3341A>G	p.Asp1114Gly	missense_variant, splice_region_variant	22/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.3341A>G	p.Asp1114Gly	missense_variant, splice_region_variant	22/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3763 AN: 152178 Hom.: 124 Cov.: 31

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00836 AC: 2070 AN: 247588 Hom.: 54 AF XY: 0.00709 AC XY: 952 AN XY: 134324

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000365

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00455 AC: 6640 AN: 1458706 Hom.: 141 Cov.: 29 AF XY: 0.00424 AC XY: 3075 AN XY: 725684

Gnomad4 AFR exome AF: 0.0857

Gnomad4 AMR exome AF: 0.00910

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000536

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0248 AC: 3774 AN: 152296 Hom.: 124 Cov.: 31 AF XY: 0.0240 AC XY: 1790 AN XY: 74480

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00717 Hom.: 37

Bravo AF: 0.0277

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0742 AC: 282

ESP6500EA AF: 0.00425 AC: 35

ExAC AF: 0.00911 AC: 1101

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Leber congenital amaurosis 6 Pathogenic:1 Benign:1

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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2005	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	This variant is associated with the following publications: (PMID: 20981092, 27884173, 15800011, 11528500, 16272259, 29343940) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.068
DANN	Benign	0.84
DEOGEN2	Benign	0.057	T;T;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.49	T;T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0023	A;A;A;A;A;A;A
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.0070, 0.039, 0.0030	.;.;B;B;B
Vest4		0.11
MVP		0.65
MPC		0.086
ClinPred		0.0063	T
GERP RS		-1.8
Varity_R		0.16
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.020		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: rs17103671; hg19: chr14-21811196; COSMIC: COSV52847485;