14-21327686-G-A

Variant names:

• chr14-21327686-G-A
• NM_020366.4:c.2774G>A
• RPGRIP1 p.Trp925*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020366.4(RPGRIP1):​c.2774G>A​(p.Trp925*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPGRIP1 NM_020366.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97
• 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 10 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

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.2774G>A	p.Trp925*	stop_gained	Exon 18 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.1700G>A	p.Trp567*	stop_gained	Exon 8 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.860G>A	p.Trp287*	stop_gained	Exon 6 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.2774G>A	p.Trp925*	stop_gained	Exon 18 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.1199G>A	p.Trp400*	stop_gained	Exon 6 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.752G>A	p.Trp251*	stop_gained	Exon 5 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.0
Mutation Taster		=1/199	disease causing (fs/PTC)

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

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

Other links and lift over

hg19: chr14-21795845;