rs77775126

Positions:

• chr8-54625000-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006269.2(RP1):​c.1118C>T​(p.Thr373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,614,112 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.013 (200 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 0.856

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04813701).
• BP6: Variant 8-54625000-C-T is Benign according to our data. Variant chr8-54625000-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 5970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54625000-C-T is described in Lovd as [Benign]. Variant chr8-54625000-C-T is described in Lovd as [Pathogenic]. Variant chr8-54625000-C-T is described in Lovd as [Likely_benign]. Variant chr8-54625000-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0105 (1593/152266) while in subpopulation SAS AF= 0.024 (116/4824). AF 95% confidence interval is 0.0205. There are 19 homozygotes in gnomad4. There are 754 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2	c.1118C>T	p.Thr373Ile	missense_variant	4/4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000220676.2	c.1118C>T	p.Thr373Ile	missense_variant	4/4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.787+2712C>T		intron_variant		5		ENSP00000490104.1
RP1	ENST00000636932.1	c.787+2712C>T		intron_variant		5		ENSP00000489857.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1598 AN: 152148 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0125 AC: 3153 AN: 251296 Hom.: 40 AF XY: 0.0139 AC XY: 1887 AN XY: 135830

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0258

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0135 AC: 19670 AN: 1461846 Hom.: 200 Cov.: 34 AF XY: 0.0139 AC XY: 10117 AN XY: 727212

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0254

Gnomad4 FIN exome AF: 0.00462

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 152266 Hom.: 19 Cov.: 32 AF XY: 0.0101 AC XY: 754 AN XY: 74460

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0145 Hom.: 24

Bravo AF: 0.0102

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0127 AC: 1543

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 1 Pathogenic:1 Benign:3

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Thr373Ile variant in RP1 has been identified in at least 2 individuals with autosomal recessive retinitis pigmentosa (PMID: 15863674), but has also been identified in >2% of South Asian chromosomes and 23 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive retinitis pigmentosa. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 06, 2022	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	Reported in the heterozygous state in an individual with autosomal dominant retinitis pigmentosa (adRP); however, this variant failed to co-segregate with the disease in other affected family members. In addition, this variant was observed in 2/95 control individuals, leading the authors to suggest this is a benign variant (Berson et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15863674, 11527933, 21147909, 25097241, 11095597, 24705292, 24123366, 25333069, 27884173, 27535533) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RP1: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 12, 2014

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Benign	0.97
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.034
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.072	T
Polyphen		0.013	B
Vest4		0.012
MPC		0.049
ClinPred		0.027	T
GERP RS		-0.21
Varity_R		0.12
gMVP		0.17

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: rs77775126; hg19: chr8-55537560;