GeneBe

rs773894295

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_178857.6(RP1L1):​c.3956_3957insAAGAAGAGTG​(p.Val1320ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,365,078 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 19)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RP1L1
NM_178857.6 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.28

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • occult macular dystrophy
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
  • retinitis pigmentosa
    Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
  • retinitis pigmentosa 88
    Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • cone dystrophy
    Inheritance: AR Classification: LIMITED Submitted by: G2P

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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 15 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RP1L1NM_178857.6 linkc.3956_3957insAAGAAGAGTG 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
RP1L1ENST00000382483.4 linkc.3956_3957insAAGAAGAGTG p.Val1320ArgfsTer10 frameshift_variant Exon 4 of 4 1 NM_178857.6 ENSP00000371923.3 Q8IWN7-1

Frequencies

GnomAD3 genomes
Cov.:
19
GnomAD4 exome
AF:
7.33e-7
AC:
1
AN:
1365078
Hom.:
0
Cov.:
38
AF XY:
0.00
AC XY:
0
AN XY:
677906
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31064
American (AMR)
AF:
0.00
AC:
0
AN:
37472
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24040
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79672
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
45946
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5488
European-Non Finnish (NFE)
AF:
9.47e-7
AC:
1
AN:
1056504
Other (OTH)
AF:
0.00
AC:
0
AN:
55192
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-4.3

Splicing

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

Publications

Other links and lift over

dbSNP: rs773894295; hg19: chr8-10467651; API