chr8-54626835-A-T

Variant names:

• chr8-54626835-A-T
• rs2293869
• NM_006269.2:c.2953A>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.2953A>T​(p.Asn985Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,613,258 control chromosomes in the GnomAD database, including 125,356 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9212 hom., cov: 32)
  • Exomes 𝑓: 0.39 (116144 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.80
• Publications: 47 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=8.9737773E-4).
• BP6: Variant 8-54626835-A-T is Benign according to our data. Variant chr8-54626835-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 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.2953A>T	p.Asn985Tyr	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+4547A>T		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.2953A>T	p.Asn985Tyr	missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+4547A>T		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+4547A>T		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50429 AN: 151910 Hom.: 9206 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.0666

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.343 AC: 86181 AN: 251018 AF XY: 0.356

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.0606

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.390 AC: 570231 AN: 1461230 Hom.: 116144 Cov.: 56 AF XY: 0.391 AC XY: 284389 AN XY: 726936

African (AFR) AF: 0.214 AC: 7167 AN: 33480

American (AMR) AF: 0.211 AC: 9447 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 13790 AN: 26128

East Asian (EAS) AF: 0.0866 AC: 3437 AN: 39684

South Asian (SAS) AF: 0.344 AC: 29684 AN: 86248

European-Finnish (FIN) AF: 0.407 AC: 21624 AN: 53132

Middle Eastern (MID) AF: 0.470 AC: 2710 AN: 5766

European-Non Finnish (NFE) AF: 0.413 AC: 459305 AN: 1111680

Other (OTH) AF: 0.382 AC: 23067 AN: 60388

GnomAD4 genome AF: 0.332 AC: 50443 AN: 152028 Hom.: 9212 Cov.: 32 AF XY: 0.329 AC XY: 24428 AN XY: 74304

African (AFR) AF: 0.216 AC: 8972 AN: 41484

American (AMR) AF: 0.270 AC: 4128 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1862 AN: 3470

East Asian (EAS) AF: 0.0667 AC: 345 AN: 5170

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4814

European-Finnish (FIN) AF: 0.400 AC: 4223 AN: 10556

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28049 AN: 67934

Other (OTH) AF: 0.358 AC: 755 AN: 2110

Alfa AF: 0.390 Hom.: 9046

Bravo AF: 0.317

TwinsUK AF: 0.424 AC: 1571

ALSPAC AF: 0.409 AC: 1576

ESP6500AA AF: 0.214 AC: 944

ESP6500EA AF: 0.417 AC: 3584

ExAC AF: 0.347 AC: 42142

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hypertriglyceridemia 1 (1)
-	-	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	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00090	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.11
MPC		0.19
ClinPred		0.027	T
GERP RS		1.9
Varity_R		0.26
gMVP		0.29
Mutation Taster		=98/2	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: rs2293869; hg19: chr8-55539395; COSMIC: COSV55112021;