rs2064317

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_003322.6(TULP1):c.776T>C(p.Ile259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,612,918 control chromosomes in the GnomAD database, including 119,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10494 hom., cov: 31)

Exomes 𝑓: 0.38 ( 109066 hom. )

Consequence

TULP1
NM_003322.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.854

Publications

35 publications found

Variant links:

Genes affected

TULP1 (HGNC:12423): (TUB like protein 1) This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]

TULP1 Gene-Disease associations (from GenCC):

retinitis pigmentosa 14
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 15
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TULP1 links:

ENSG00000228559 (HGNC:58100):

ENSG00000228559 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.64726 (below the threshold of 3.09). Trascript score misZ: -0.4024 (below the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa, retinitis pigmentosa 14, Leber congenital amaurosis 15, Leber congenital amaurosis.

BP4

Computational evidence support a benign effect (MetaRNN=6.7973137E-4).

BP6

Variant 6-35509255-A-G is Benign according to our data. Variant chr6-35509255-A-G is described in ClinVar as Benign. ClinVar VariationId is 99671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6 link	c.776T>C	p.Ile259Thr	missense_variant	Exon 8 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2 link	c.617T>C	p.Ile206Thr	missense_variant	Exon 7 of 14		NP_001276324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11 link	c.776T>C	p.Ile259Thr	missense_variant	Exon 8 of 15	1	NM_003322.6	ENSP00000229771.6

Frequencies

GnomAD3 genomes

AF:

0.369

AC:

55979

AN:

151560

Hom.:

10488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.500

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.137

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.313

GnomAD2 exomes

AF:

0.381

AC:

95819

AN:

251456

AF XY:

0.380

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.493

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.376

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.384

AC:

560422

AN:

1461240

Hom.:

109066

Cov.:

AF XY:

0.382

AC XY:

278027

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.347

AC:

11608

AN:

33472

American (AMR)

AF:

0.359

AC:

16064

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

6651

AN:

26128

East Asian (EAS)

AF:

0.434

AC:

17236

AN:

39698

South Asian (SAS)

AF:

0.418

AC:

36052

AN:

86244

European-Finnish (FIN)

AF:

0.388

AC:

20726

AN:

53396

Middle Eastern (MID)

AF:

0.209

AC:

1205

AN:

5766

European-Non Finnish (NFE)

AF:

0.385

AC:

427851

AN:

1111432

Other (OTH)

AF:

0.381

AC:

23029

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

20091

40182

60274

80365

100456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13516

27032

40548

54064

67580

<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:

0.369

AC:

56013

AN:

151678

Hom.:

10494

Cov.:

AF XY:

0.372

AC XY:

27569

AN XY:

74094

show subpopulations

African (AFR)

AF:

0.346

AC:

14306

AN:

41318

American (AMR)

AF:

0.353

AC:

5382

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

916

AN:

3470

East Asian (EAS)

AF:

0.499

AC:

2548

AN:

5104

South Asian (SAS)

AF:

0.434

AC:

2090

AN:

4812

European-Finnish (FIN)

AF:

0.384

AC:

4038

AN:

10514

Middle Eastern (MID)

AF:

0.137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.379

AC:

25733

AN:

67900

Other (OTH)

AF:

0.316

AC:

667

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1834

3668

5502

7336

9170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.373

Hom.:

23777

Bravo

AF:

0.362

TwinsUK

AF:

0.383

AC:

1420

ALSPAC

AF:

0.385

AC:

1484

ESP6500AA

AF:

0.355

AC:

1564

ESP6500EA

AF:

0.371

AC:

3190

ExAC

AF:

0.384

AC:

46659

Asia WGS

AF:

0.429

AC:

1494

AN:

3478

EpiCase

AF:

0.351

EpiControl

AF:

0.344

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Leber congenital amaurosis 15

Benign:2

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 03, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 14

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

6.1

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.044

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.18

T;T;T

MetaRNN

Benign

0.00068

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.9

.;N;.

PhyloP100

0.85

PrimateAI

Benign

0.41

PROVEAN

Benign

2.1

N;N;.

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.10

MPC

0.33

ClinPred

0.0036

GERP RS

3.6

Varity_R

0.037

gMVP

0.031

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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