NM_178857.6:c.335C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_178857.6(RP1L1):c.335C>G(p.Thr112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0363 in 1,613,054 control chromosomes in the GnomAD database, including 17,275 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T112I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 9086 hom., cov: 31)

Exomes 𝑓: 0.020 ( 8189 hom. )

Consequence

RP1L1
NM_178857.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.60

Publications

9 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=9.029263E-6).

BP6

Variant 8-10622867-G-C is Benign according to our data. Variant chr8-10622867-G-C is described in ClinVar as Benign. ClinVar VariationId is 361416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1L1	NM_178857.6 link	c.335C>G	p.Thr112Ser	missense_variant	Exon 2 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.335C>G	p.Thr112Ser	missense_variant	Exon 2 of 4	1	NM_178857.6	ENSP00000371923.3		Q8IWN7-1
RP1L1	ENST00000329335.3 link	n.585C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28692

AN:

151924

Hom.:

9051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0799

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.0477

AC:

11668

AN:

244860

AF XY:

0.0361

show subpopulations

Gnomad AFR exome

AF:

0.674

Gnomad AMR exome

AF:

0.0344

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0204

AC:

29849

AN:

1461012

Hom.:

8189

Cov.:

AF XY:

0.0176

AC XY:

12809

AN XY:

726720

show subpopulations

African (AFR)

AF:

0.678

AC:

22667

AN:

33450

American (AMR)

AF:

0.0401

AC:

1792

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

400

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00228

AC:

197

AN:

86234

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.0366

AC:

211

AN:

5762

European-Non Finnish (NFE)

AF:

0.00165

AC:

1836

AN:

1111458

Other (OTH)

AF:

0.0455

AC:

2744

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

814

1628

2441

3255

4069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.189

AC:

28780

AN:

152042

Hom.:

9086

Cov.:

AF XY:

0.184

AC XY:

13674

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.653

AC:

27017

AN:

41374

American (AMR)

AF:

0.0797

AC:

1219

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00394

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00271

AC:

184

AN:

68014

Other (OTH)

AF:

0.132

AC:

279

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

547

1093

1640

2186

2733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.0306

Hom.:

920

Bravo

AF:

0.217

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.572

AC:

2202

ESP6500EA

AF:

0.00412

AC:

ExAC

AF:

0.0575

AC:

6934

Asia WGS

AF:

0.0360

AC:

126

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00374

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Occult macular dystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.16

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.090

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0000090

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

PhyloP100

4.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

REVEL

Benign

0.23

Sift

Benign

0.079

Sift4G

Uncertain

0.027

Vest4

0.37

MutPred

0.29

Gain of glycosylation at P113 (P = 0.097);

ClinPred

0.016

GERP RS

3.9

Varity_R

0.067

gMVP

0.15

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over