Genetic Variant RP1L1:p.Val1320ArgfsTer10 (chr8-10610141-C-CCTCTCTTCTT) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_StrongBP6BA1

The NM_178857.6(RP1L1):c.3956_3957insAAGAAGAGAG(p.Val1320ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.077 ( 711 hom., cov: 19)

Exomes 𝑓: 0.048 ( 6253 hom. )

Failed GnomAD Quality Control

Consequence

RP1L1
NM_178857.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -4.28

Variant links:

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]

RP1L1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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 10 pathogenic variants in the truncated region.

BP6

Variant 8-10610141-C-CCTCTCTTCTT is Benign according to our data. Variant chr8-10610141-C-CCTCTCTTCTT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225459.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1L1	NM_178857.6 link	c.3956_3957insAAGAAGAGAG	p.Val1320ArgfsTer10	frameshift_variant	Exon 4 of 4	ENST00000382483.4	NP_849188.4	Q8IWN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1L1	ENST00000382483.4 link	c.3956_3957insAAGAAGAGAG	p.Val1320ArgfsTer10	frameshift_variant	Exon 4 of 4	1	NM_178857.6	ENSP00000371923.3		Q8IWN7-1

Frequencies

GnomAD3 genomes

AF:

0.0767

AC:

11389

AN:

148502

Hom.:

711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0387

Gnomad AMR

AF:

0.0655

Gnomad ASJ

AF:

0.0959

Gnomad EAS

AF:

0.00891

Gnomad SAS

AF:

0.0616

Gnomad FIN

AF:

0.0281

Gnomad MID

AF:

0.0942

Gnomad NFE

AF:

0.0728

Gnomad OTH

AF:

0.0906

GnomAD3 exomes

AF:

0.0406

AC:

9879

AN:

243342

Hom.:

678

AF XY:

0.0406

AC XY:

5367

AN XY:

132050

show subpopulations

Gnomad AFR exome

AF:

0.0811

Gnomad AMR exome

AF:

0.0273

Gnomad ASJ exome

AF:

0.0708

Gnomad EAS exome

AF:

0.00559

Gnomad SAS exome

AF:

0.0447

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0503

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0480

AC:

63802

AN:

1328278

Hom.:

6253

Cov.:

AF XY:

0.0491

AC XY:

32429

AN XY:

660322

show subpopulations

Gnomad4 AFR exome

AF:

0.0995

Gnomad4 AMR exome

AF:

0.0417

Gnomad4 ASJ exome

AF:

0.0950

Gnomad4 EAS exome

AF:

0.0331

Gnomad4 SAS exome

AF:

0.0592

Gnomad4 FIN exome

AF:

0.0415

Gnomad4 NFE exome

AF:

0.0447

Gnomad4 OTH exome

AF:

0.0612

GnomAD4 genome

AF:

0.0767

AC:

11397

AN:

148618

Hom.:

711

Cov.:

AF XY:

0.0736

AC XY:

5350

AN XY:

72672

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.0655

Gnomad4 ASJ

AF:

0.0959

Gnomad4 EAS

AF:

0.00894

Gnomad4 SAS

AF:

0.0614

Gnomad4 FIN

AF:

0.0281

Gnomad4 NFE

AF:

0.0728

Gnomad4 OTH

AF:

0.0895

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Occult macular dystrophy

Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not specified

Benign:1

May 04, 2022

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over