NM_006269.2:c.5175A>G

Variant names:

• chr8-54629057-A-G
• rs441800
• NM_006269.2:c.5175A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006269.2(RP1):​c.5175A>G​(p.Gln1725Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,962 control chromosomes in the GnomAD database, including 53,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4156 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49393 hom.)
• Consequence: RP1 NM_006269.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.663
• Publications: 28 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-54629057-A-G is Benign according to our data. Variant chr8-54629057-A-G is described in ClinVar as Benign. ClinVar VariationId is 95355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.663 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 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.5175A>G	p.Gln1725Gln	synonymous	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+6769A>G		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.5175A>G	p.Gln1725Gln	synonymous	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+6769A>G		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+6769A>G		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32558 AN: 152056 Hom.: 4148 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.246

GnomAD2 exomes AF: 0.258 AC: 64790 AN: 251318 AF XY: 0.257

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.255 AC: 373326 AN: 1461788 Hom.: 49393 Cov.: 56 AF XY: 0.255 AC XY: 185330 AN XY: 727198

African (AFR) AF: 0.0769 AC: 2573 AN: 33478

American (AMR) AF: 0.310 AC: 13864 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5975 AN: 26132

East Asian (EAS) AF: 0.405 AC: 16092 AN: 39698

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

European-Finnish (FIN) AF: 0.204 AC: 10898 AN: 53414

Middle Eastern (MID) AF: 0.263 AC: 1515 AN: 5768

European-Non Finnish (NFE) AF: 0.258 AC: 286751 AN: 1111928

Other (OTH) AF: 0.252 AC: 15198 AN: 60392

GnomAD4 genome AF: 0.214 AC: 32589 AN: 152174 Hom.: 4156 Cov.: 32 AF XY: 0.214 AC XY: 15933 AN XY: 74396

African (AFR) AF: 0.0808 AC: 3354 AN: 41532

American (AMR) AF: 0.312 AC: 4770 AN: 15276

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

East Asian (EAS) AF: 0.422 AC: 2182 AN: 5174

South Asian (SAS) AF: 0.237 AC: 1142 AN: 4816

European-Finnish (FIN) AF: 0.205 AC: 2171 AN: 10600

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17383 AN: 67984

Other (OTH) AF: 0.249 AC: 526 AN: 2116

Alfa AF: 0.248 Hom.: 7803

Bravo AF: 0.217

Asia WGS AF: 0.317 AC: 1102 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
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.25
DANN	Benign	0.73
PhyloP100		0.66
Mutation Taster		=100/0	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: rs441800; hg19: chr8-55541617; COSMIC: COSV55113695;