chr8-54626497-G-A

Variant names:

• chr8-54626497-G-A
• rs444772
• NM_006269.2:c.2615G>A

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.2615G>A​(p.Arg872His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,004 control chromosomes in the GnomAD database, including 60,244 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R872C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5112 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55132 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.78
• 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=0.0014749765).
• BP6: Variant 8-54626497-G-A is Benign according to our data. Variant chr8-54626497-G-A is described in ClinVar as Benign. ClinVar VariationId is 167602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 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.2615G>A	p.Arg872His	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+4209G>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.2615G>A	p.Arg872His	missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+4209G>A		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+4209G>A		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37833 AN: 151512 Hom.: 5104 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.285

GnomAD2 exomes AF: 0.276 AC: 68980 AN: 249880 AF XY: 0.274

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.271 AC: 396612 AN: 1461374 Hom.: 55132 Cov.: 38 AF XY: 0.271 AC XY: 196707 AN XY: 726994

African (AFR) AF: 0.164 AC: 5503 AN: 33472

American (AMR) AF: 0.328 AC: 14660 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6123 AN: 26126

East Asian (EAS) AF: 0.405 AC: 16067 AN: 39662

South Asian (SAS) AF: 0.247 AC: 21320 AN: 86246

European-Finnish (FIN) AF: 0.215 AC: 11481 AN: 53354

Middle Eastern (MID) AF: 0.304 AC: 1754 AN: 5764

European-Non Finnish (NFE) AF: 0.273 AC: 303322 AN: 1111662

Other (OTH) AF: 0.271 AC: 16382 AN: 60370

GnomAD4 genome AF: 0.250 AC: 37868 AN: 151630 Hom.: 5112 Cov.: 31 AF XY: 0.249 AC XY: 18473 AN XY: 74066

African (AFR) AF: 0.166 AC: 6877 AN: 41392

American (AMR) AF: 0.345 AC: 5249 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 809 AN: 3460

East Asian (EAS) AF: 0.421 AC: 2146 AN: 5098

South Asian (SAS) AF: 0.247 AC: 1190 AN: 4812

European-Finnish (FIN) AF: 0.214 AC: 2234 AN: 10440

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18465 AN: 67898

Other (OTH) AF: 0.287 AC: 604 AN: 2102

Alfa AF: 0.273 Hom.: 20886

Bravo AF: 0.256

TwinsUK AF: 0.274 AC: 1017

ALSPAC AF: 0.265 AC: 1020

ESP6500AA AF: 0.169 AC: 743

ESP6500EA AF: 0.271 AC: 2330

ExAC AF: 0.270 AC: 32708

Asia WGS AF: 0.326 AC: 1133 AN: 3474

EpiCase AF: 0.280

EpiControl AF: 0.278

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.079
Sift	Benign	0.031	D
Sift4G	Uncertain	0.047	D
Polyphen		0.24	B
Vest4		0.042
MPC		0.062
ClinPred		0.015	T
GERP RS		1.4
Varity_R		0.038
gMVP		0.092
Mutation Taster		=87/13	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: rs444772; hg19: chr8-55539057; COSMIC: COSV55126143;