rs73201156

Positions:

chr8-10610143-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000382483.4(RP1L1):c.3955G>A(p.Ala1319Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 817,348 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1319G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0052 ( 5 hom., cov: 20)

Exomes 𝑓: 0.0058 ( 107 hom. )

Consequence

RP1L1
ENST00000382483.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.249

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030745268).

BP6

Variant 8-10610143-C-T is Benign according to our data. Variant chr8-10610143-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 361301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-10610143-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00516 (388/75210) while in subpopulation SAS AF= 0.011 (31/2814). AF 95% confidence interval is 0.00935. There are 5 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1L1	NM_178857.6 linkuse as main transcript	c.3955G>A	p.Ala1319Thr	missense_variant	4/4	ENST00000382483.4	NP_849188.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP1L1	ENST00000382483.4 linkuse as main transcript	c.3955G>A	p.Ala1319Thr	missense_variant	4/4	1	NM_178857.6	ENSP00000371923	P1	Q8IWN7-1

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

390

AN:

75110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00261

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.00195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00208

GnomAD3 exomes

AF:

0.0150

AC:

1966

AN:

131088

Hom.:

AF XY:

0.0159

AC XY:

1113

AN XY:

69934

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.00535

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.000460

Gnomad SAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00576

AC:

4274

AN:

742138

Hom.:

107

Cov.:

AF XY:

0.00584

AC XY:

2202

AN XY:

377036

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.00420

Gnomad4 ASJ exome

AF:

0.00674

Gnomad4 EAS exome

AF:

0.000131

Gnomad4 SAS exome

AF:

0.00909

Gnomad4 FIN exome

AF:

0.00443

Gnomad4 NFE exome

AF:

0.00565

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.00516

AC:

388

AN:

75210

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

215

AN XY:

38086

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.00195

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.00203

Alfa

AF:

0.0541

Hom.:

ExAC

AF:

0.0399

AC:

4560

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (fails quality filter) -

Occult macular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Occult macular dystrophy;C5394208:Retinitis pigmentosa 88

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.4

DANN

Benign

0.29

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.0

REVEL

Benign

0.014

Sift

Benign

0.48

Sift4G

Benign

0.58

Vest4

0.026

ClinPred

0.00037

GERP RS

0.064

Varity_R

0.028

gMVP

0.050

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

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