rs28664100

Positions:

• chr14-21343021-C-T

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.3340-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00915 in 1,604,446 control chromosomes in the GnomAD database, including 1,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (625 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (545 hom.)
• Consequence: RPGRIP1 NM_020366.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.814

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=-0.88).
• BP6: Variant 14-21343021-C-T is Benign according to our data. Variant chr14-21343021-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.3340-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.3340-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7446 AN: 152096 Hom.: 621 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0127 AC: 3135 AN: 246842 Hom.: 245 AF XY: 0.00941 AC XY: 1260 AN XY: 133968

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.00899

Gnomad ASJ exome AF: 0.000905

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000466

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000472

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.00497 AC: 7212 AN: 1452232 Hom.: 545 Cov.: 28 AF XY: 0.00424 AC XY: 3067 AN XY: 722686

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000386

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0491 AC: 7471 AN: 152214 Hom.: 625 Cov.: 31 AF XY: 0.0473 AC XY: 3522 AN XY: 74430

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0282 Hom.: 37

Bravo AF: 0.0566

Asia WGS AF: 0.0130 AC: 45 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

PreventionGenetics, part of Exact Sciences

-

- -

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

Nov 20, 2018

- -

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). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.69

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: rs28664100; hg19: chr14-21811180;