chr8-10610143-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178857.6(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. 14/20 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
NM_178857.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.249

Publications

15 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 361301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178857.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	NM_178857.6	MANE Select	c.3955G>A	p.Ala1319Thr	missense	Exon 4 of 4	NP_849188.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	ENST00000382483.4	TSL:1 MANE Select	c.3955G>A	p.Ala1319Thr	missense	Exon 4 of 4	ENSP00000371923.3

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

GnomAD2 exomes

AF:

0.0150

AC:

1966

AN:

131088

AF XY:

0.0159

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0120

AC:

290

AN:

24160

American (AMR)

AF:

0.00420

AC:

149

AN:

35440

Ashkenazi Jewish (ASJ)

AF:

0.00674

AC:

101

AN:

14984

East Asian (EAS)

AF:

0.000131

AC:

AN:

38216

South Asian (SAS)

AF:

0.00909

AC:

596

AN:

65598

European-Finnish (FIN)

AF:

0.00443

AC:

156

AN:

35178

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

3250

European-Non Finnish (NFE)

AF:

0.00565

AC:

2774

AN:

491140

Other (OTH)

AF:

0.00530

AC:

181

AN:

34172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00516

AC:

388

AN:

75210

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

215

AN XY:

38086

show subpopulations

African (AFR)

AF:

0.0104

AC:

272

AN:

26254

American (AMR)

AF:

0.00261

AC:

AN:

8818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1298

East Asian (EAS)

AF:

0.00

AC:

AN:

4906

South Asian (SAS)

AF:

0.0110

AC:

AN:

2814

European-Finnish (FIN)

AF:

0.00195

AC:

AN:

5638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

118

European-Non Finnish (NFE)

AF:

0.00204

AC:

AN:

23998

Other (OTH)

AF:

0.00203

AC:

AN:

984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0340

Hom.:

ExAC

AF:

0.0399

AC:

4560

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Occult macular dystrophy (1)

Occult macular dystrophy;C5394208:Retinitis pigmentosa 88 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.4

(source)

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

PhyloP100

0.25

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over