chr8-54673346-C-T

Variant names:

• chr8-54673346-C-T
• rs453186
• ENST00000637698.1:c.1324-504C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000637698.1(RP1):​c.1324-504C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,070 control chromosomes in the GnomAD database, including 4,282 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4282 hom., cov: 33)
• Consequence: RP1 ENST00000637698.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 4 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):

• RP1-related dominant retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• retinitis pigmentosa 1

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_001375654.1	c.1324-504C>T		intron_variant	Intron 7 of 29		NP_001362583.1
RP1	XM_047422069.1	c.1345-504C>T		intron_variant	Intron 8 of 29		XP_047278025.1
RP1	XM_047422070.1	c.1345-504C>T		intron_variant	Intron 8 of 29		XP_047278026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000637698.1	c.1324-504C>T		intron_variant	Intron 7 of 28	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.1324-504C>T		intron_variant	Intron 7 of 22	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33503 AN: 151950 Hom.: 4273 Cov.: 33

Gnomad AFR AF: 0.0998

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.221 AC: 33537 AN: 152070 Hom.: 4282 Cov.: 33 AF XY: 0.221 AC XY: 16414 AN XY: 74330

African (AFR) AF: 0.100 AC: 4159 AN: 41472

American (AMR) AF: 0.320 AC: 4879 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3470

East Asian (EAS) AF: 0.423 AC: 2184 AN: 5166

South Asian (SAS) AF: 0.240 AC: 1156 AN: 4820

European-Finnish (FIN) AF: 0.206 AC: 2176 AN: 10568

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

European-Non Finnish (NFE) AF: 0.256 AC: 17385 AN: 67986

Other (OTH) AF: 0.254 AC: 538 AN: 2116

Alfa AF: 0.232 Hom.: 751

Bravo AF: 0.225

Asia WGS AF: 0.319 AC: 1109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-0.27

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs453186; hg19: chr8-55585906;