rs446227

Variant names:

• chr8-54628890-G-A
• rs446227
• NM_006269.2:c.5008G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-54628890-G-A
• chr8-54628890-G-C
• chr8-54628890-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006269.2(RP1):​c.5008G>A​(p.Ala1670Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,814 control chromosomes in the GnomAD database, including 53,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4272 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49563 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: -0.0880
• Publications: 46 publications found

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]

RP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Illumina
• RP1-related dominant retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• RP1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7616153E-4).
• BP6: Variant 8-54628890-G-A is Benign according to our data. Variant chr8-54628890-G-A is described in ClinVar as Benign. ClinVar VariationId is 95352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006269.2. 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
	RP1	NM_006269.2	MANE Select	c.5008G>A	p.Ala1670Thr	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+6602G>A		intron	N/A	NP_001362583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	ENST00000220676.2	TSL:1 MANE Select	c.5008G>A	p.Ala1670Thr	missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+6602G>A		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+6602G>A		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33457 AN: 151910 Hom.: 4263 Cov.: 32

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.259 AC: 65151 AN: 251166 AF XY: 0.258

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.256 AC: 374369 AN: 1461786 Hom.: 49563 Cov.: 67 AF XY: 0.256 AC XY: 185803 AN XY: 727202

African (AFR) AF: 0.0974 AC: 3262 AN: 33480

American (AMR) AF: 0.312 AC: 13959 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5976 AN: 26134

East Asian (EAS) AF: 0.405 AC: 16087 AN: 39698

South Asian (SAS) AF: 0.237 AC: 20460 AN: 86256

European-Finnish (FIN) AF: 0.204 AC: 10895 AN: 53414

Middle Eastern (MID) AF: 0.268 AC: 1546 AN: 5768

European-Non Finnish (NFE) AF: 0.258 AC: 286850 AN: 1111916

Other (OTH) AF: 0.254 AC: 15334 AN: 60396

GnomAD4 genome AF: 0.220 AC: 33490 AN: 152028 Hom.: 4272 Cov.: 32 AF XY: 0.220 AC XY: 16381 AN XY: 74310

African (AFR) AF: 0.100 AC: 4152 AN: 41482

American (AMR) AF: 0.319 AC: 4876 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3472

East Asian (EAS) AF: 0.420 AC: 2168 AN: 5162

South Asian (SAS) AF: 0.237 AC: 1139 AN: 4808

European-Finnish (FIN) AF: 0.205 AC: 2172 AN: 10570

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17385 AN: 67946

Other (OTH) AF: 0.254 AC: 537 AN: 2112

Alfa AF: 0.254 Hom.: 23282

Bravo AF: 0.225

TwinsUK AF: 0.259 AC: 960

ALSPAC AF: 0.253 AC: 975

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.256 AC: 2199

ExAC AF: 0.253 AC: 30695

Asia WGS AF: 0.319 AC: 1109 AN: 3478

EpiCase AF: 0.262

EpiControl AF: 0.260

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Retinitis pigmentosa 1 (2)
1	-	-	Autosomal recessive retinitis pigmentosa (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.39
DANN	Benign	0.59
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.088
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.018
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.011	B
Vest4		0.013
MPC		0.029
ClinPred		0.0032	T
GERP RS		-0.33
Varity_R		0.043
gMVP		0.066
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs446227; hg19: chr8-55541450; COSMIC: COSV55122630;