rs201538234

Positions:

• chr8-54626598-G-A
• chr8-54626598-G-C
• chr8-54626598-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006269.2(RP1):​c.2716G>A​(p.Ala906Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A906P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.666

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015234679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1	NM_006269.2	c.2716G>A	p.Ala906Thr	missense_variant	4/4	ENST00000220676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1	ENST00000220676.2	c.2716G>A	p.Ala906Thr	missense_variant	4/4	1	NM_006269.2
RP1	ENST00000636932.1	c.787+4310G>A		intron_variant		5
RP1	ENST00000637698.1	c.787+4310G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 249938 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461336 Hom.: 0 Cov.: 36 AF XY: 0.0000564 AC XY: 41 AN XY: 726964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 23, 2018	The RP1 c.2716G>A; p.Ala906Thr variant (rs201538234), to our knowledge, is not reported in the medical literature. The variant is reported in the ClinVar database (Variation ID: 167603) and in the general population with an overall allele frequency of 0.01% (29/276206 alleles) in the Genome Aggregation Database. The alanine at codon 906 is weakly conserved but computational analyses predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic RP1 variants are causative for autosomal dominant or recessive retinitis pigmentosa (MIM: 180100). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 906 of the RP1 protein (p.Ala906Thr). This variant is present in population databases (rs201538234, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167603). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2014	- -

Retinitis pigmentosa 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.066
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.30	T
Polyphen		0.0070	B
Vest4		0.039
MVP		0.51
MPC		0.034
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.090
gMVP		0.099

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: rs201538234; hg19: chr8-55539158;