rs863223340

Positions:

• chr8-54622180-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_006269.2(RP1):​c.679T>G​(p.Phe227Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Doublecortin 2 (size 79) in uniprot entity RP1_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_006269.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 8-54622180-T-G is Pathogenic according to our data. Variant chr8-54622180-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 191355.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-54622180-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2	c.679T>G	p.Phe227Val	missense_variant	3/4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000220676.2	c.679T>G	p.Phe227Val	missense_variant	3/4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.679T>G	p.Phe227Val	missense_variant	3/29	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.679T>G	p.Phe227Val	missense_variant	3/23	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences

Jan 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.9	.;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	.;D;.
Vest4		0.65
MutPred		0.91		Gain of ubiquitination at K228 (P = 0.0725);Gain of ubiquitination at K228 (P = 0.0725);Gain of ubiquitination at K228 (P = 0.0725);
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.78

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: rs863223340; hg19: chr8-55534740;