rs1555303320

Variant names:

• chr14-21330269-G-A
• rs1555303320
• NM_020366.4:c.3120G>A
• RPGRIP1 p.Trp1040*

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020366.4(RPGRIP1):​c.3120G>A​(p.Trp1040*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: RPGRIP1 NM_020366.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.65
• 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, STRONG Submitted by: PanelApp Australia, G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-21330269-G-A is Pathogenic according to our data. Variant chr14-21330269-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438164.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.3120G>A	p.Trp1040*	stop_gained	Exon 20 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2046G>A	p.Trp682*	stop_gained	Exon 10 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1206G>A	p.Trp402*	stop_gained	Exon 8 of 13	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.3120G>A	p.Trp1040*	stop_gained	Exon 20 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.1545G>A	p.Trp515*	stop_gained	Exon 8 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.1098G>A	p.Trp366*	stop_gained	Exon 7 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leber congenital amaurosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		2.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -20

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555303320;

hg19: chr14-21798428;