rs771116776

Variant names:

• chr14-21345198-G-A
• rs771116776
• NM_020366.4:c.3617+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-21345198-G-A
• chr14-21345198-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020366.4(RPGRIP1):​c.3617+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPGRIP1 NM_020366.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.55
• Publications: 0 publications found

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]

RPGRIP1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 13

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-21345198-G-A is Pathogenic according to our data. Variant chr14-21345198-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 587410.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.3617+1G>A		splice_donor intron	N/A	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2543+1G>A		splice_donor intron	N/A	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1703+1G>A		splice_donor intron	N/A	NP_001364878.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.3617+1G>A		splice_donor intron	N/A	ENSP00000382895.2
	RPGRIP1	ENST00000555587.5	TSL:1	c.2042+1G>A		splice_donor intron	N/A	ENSP00000451262.1
	RPGRIP1	ENST00000382933.8	TSL:1	c.1595+1G>A		splice_donor intron	N/A	ENSP00000372391.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod dystrophy 13 Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leber congenital amaurosis 6 Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.5
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771116776; hg19: chr14-21813357;