rs34725281

chr14-21348273-G-A

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.3719G>A(p.Gly1240Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,586,636 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (137 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (125 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.88

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=0.0024254918).
• BP6: Variant 14-21348273-G-A is Benign according to our data. Variant chr14-21348273-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.3719G>A	p.Gly1240Glu	missense_variant	24/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.3719G>A	p.Gly1240Glu	missense_variant	24/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3439 AN: 152118 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00616 AC: 1300 AN: 211026 Hom.: 49 AF XY: 0.00456 AC XY: 516 AN XY: 113126

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00250 AC: 3590 AN: 1434400 Hom.: 125 Cov.: 29 AF XY: 0.00217 AC XY: 1540 AN XY: 711102

Gnomad4 AFR exome AF: 0.0825

Gnomad4 AMR exome AF: 0.00492

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.0226 AC: 3442 AN: 152236 Hom.: 137 Cov.: 32 AF XY: 0.0216 AC XY: 1611 AN XY: 74458

Gnomad4 AFR AF: 0.0780

Gnomad4 AMR AF: 0.00812

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00697 Hom.: 43

Bravo AF: 0.0267

ESP6500AA AF: 0.0678 AC: 253

ESP6500EA AF: 0.000851 AC: 7

ExAC AF: 0.00669 AC: 807

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cone-rod dystrophy 13 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2019

- -

Leber congenital amaurosis 6 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.81	T;T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.91	D;D;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.035	D;T;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.84, 0.97, 0.90	.;.;P;D;P
Vest4		0.29
MVP		0.85
MPC		0.38
ClinPred		0.049	T
GERP RS		4.5
Varity_R		0.51
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs34725281; hg19: chr14-21816432;