8-10610141-C-CCTCTCTTCTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

2 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

RP1L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 15 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 VariationId is 225459.

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

GnomAD2 exomes

AF:

0.0406

AC:

9879

AN:

243342

AF XY:

0.0406

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 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

African (AFR)

AF:

0.0995

AC:

3051

AN:

30650

American (AMR)

AF:

0.0417

AC:

1547

AN:

37104

Ashkenazi Jewish (ASJ)

AF:

0.0950

AC:

2231

AN:

23480

East Asian (EAS)

AF:

0.0331

AC:

983

AN:

29686

South Asian (SAS)

AF:

0.0592

AC:

4679

AN:

79098

European-Finnish (FIN)

AF:

0.0415

AC:

1895

AN:

45712

Middle Eastern (MID)

AF:

0.0783

AC:

420

AN:

5366

European-Non Finnish (NFE)

AF:

0.0447

AC:

45701

AN:

1023322

Other (OTH)

AF:

0.0612

AC:

3295

AN:

53860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1651

3302

4952

6603

8254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1194

2388

3582

4776

5970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0767

AC:

11397

AN:

148618

Hom.:

711

Cov.:

AF XY:

0.0736

AC XY:

5350

AN XY:

72672

show subpopulations

African (AFR)

AF:

0.109

AC:

4327

AN:

39710

American (AMR)

AF:

0.0655

AC:

981

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.0959

AC:

326

AN:

3398

East Asian (EAS)

AF:

0.00894

AC:

AN:

5036

South Asian (SAS)

AF:

0.0614

AC:

292

AN:

4756

European-Finnish (FIN)

AF:

0.0281

AC:

291

AN:

10366

Middle Eastern (MID)

AF:

0.105

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0728

AC:

4885

AN:

67110

Other (OTH)

AF:

0.0895

AC:

185

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

345

690

1035

1380

1725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

PhyloP100

-4.3

Mutation Taster

=197/3

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over