14-21325943-G-T

Variant names:

• chr14-21325943-G-T
• rs28937883
• NM_020366.4:c.2480G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020366.4(RPGRIP1):​c.2480G>T​(p.Arg827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 1.42

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-21325943-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 14-21325943-G-T is Pathogenic according to our data. Variant chr14-21325943-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4986.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-21325943-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.2480G>T	p.Arg827Leu	missense_variant	Exon 17 of 25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.2480G>T	p.Arg827Leu	missense_variant	Exon 17 of 25	1	NM_020366.4	ENSP00000382895.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod dystrophy 13 Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy Pathogenic:1

May 27, 2024

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;D;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.99, 0.99	.;D;D
Vest4		0.84
MutPred		0.82		.;Loss of catalytic residue at R827 (P = 0.0609);.;
MVP		0.92
MPC		0.38
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.33
gMVP		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: rs28937883; hg19: chr14-21794102;