rs781490139

Positions:

• chr8-10610093-C-CA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_178857.6(RP1L1):​c.4004_4005insT​(p.Val1336fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 150,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 40)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RP1L1 NM_178857.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.894

Genes affected

RP1L1 (HGNC:15946): (RP1 like 1) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, and two C-terminal large repetitive regions, both of which contain a high percentage of glutamine and glutamic acid residues. This protein is a retinal-specific protein. Its exact length varies among individuals due to the presence of a 16aa repeat in the first C-terminal repetitive region. The 16aa repeat is encoded by the highly polymorphic 48-bp repeat, and 1-6 copies of the 16aa repeat have been identified in normal individuals. The current reference sequence shown here has a single copy of the 16aa repeat. This protein and the RP1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Mutations in this gene cause occult macular dystrophy (OMD). [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PP5: Variant 8-10610093-C-CA is Pathogenic according to our data. Variant chr8-10610093-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522779.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1L1	NM_178857.6	c.4004_4005insT	p.Val1336fs	frameshift_variant	4/4	ENST00000382483.4	NP_849188.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP1L1	ENST00000382483.4	c.4004_4005insT	p.Val1336fs	frameshift_variant	4/4	1	NM_178857.6	ENSP00000371923.3

Frequencies

GnomAD3 genomes AF: 0.000371 AC: 56 AN: 150772 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.000172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 248426 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000375 AC: 50 AN: 1334942 Hom.: 0 Cov.: 122 AF XY: 0.0000468 AC XY: 31 AN XY: 661972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000144

Gnomad4 FIN exome AF: 0.0000869

Gnomad4 NFE exome AF: 0.0000299

Gnomad4 OTH exome AF: 0.0000562

GnomAD4 genome AF: 0.000371 AC: 56 AN: 150772 Hom.: 0 Cov.: 40 AF XY: 0.000435 AC XY: 32 AN XY: 73600

Gnomad4 AFR AF: 0.000172

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.000575

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00291 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa 88 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 21, 2020

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM4. -

Occult macular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs781490139; hg19: chr8-10467603;