6-35509248-C-G

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.783G>C(p.Lys261Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,613,322 control chromosomes in the GnomAD database, including 543,689 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: 𝑓 0.84 ( 53955 hom., cov: 31)

Exomes 𝑓: 0.82 ( 489734 hom. )

Consequence

TULP1
NM_003322.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.903

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=6.118131E-7).

BP6

Variant 6-35509248-C-G is Benign according to our data. Variant chr6-35509248-C-G is described in ClinVar as Benign. ClinVar VariationId is 94127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6 link	c.783G>C	p.Lys261Asn	missense_variant	Exon 8 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2 link	c.624G>C	p.Lys208Asn	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.783G>C	p.Lys261Asn	missense_variant	Exon 8 of 15	1	NM_003322.6	ENSP00000229771.6

Frequencies

GnomAD3 genomes

AF:

0.842

AC:

127804

AN:

151838

Hom.:

53898

Cov.:

show subpopulations

Gnomad AFR

AF:

0.901

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.860

Gnomad ASJ

AF:

0.810

Gnomad EAS

AF:

0.843

Gnomad SAS

AF:

0.746

Gnomad FIN

AF:

0.787

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.818

Gnomad OTH

AF:

0.827

GnomAD2 exomes

AF:

0.823

AC:

206899

AN:

251466

AF XY:

0.815

show subpopulations

Gnomad AFR exome

AF:

0.901

Gnomad AMR exome

AF:

0.900

Gnomad ASJ exome

AF:

0.800

Gnomad EAS exome

AF:

0.840

Gnomad FIN exome

AF:

0.781

Gnomad NFE exome

AF:

0.814

Gnomad OTH exome

AF:

0.820

GnomAD4 exome

AF:

0.818

AC:

1195242

AN:

1461366

Hom.:

489734

Cov.:

AF XY:

0.815

AC XY:

592219

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.904

AC:

30260

AN:

33472

American (AMR)

AF:

0.895

AC:

40032

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.802

AC:

20961

AN:

26132

East Asian (EAS)

AF:

0.850

AC:

33730

AN:

39698

South Asian (SAS)

AF:

0.758

AC:

65349

AN:

86246

European-Finnish (FIN)

AF:

0.784

AC:

41839

AN:

53392

Middle Eastern (MID)

AF:

0.773

AC:

4459

AN:

5768

European-Non Finnish (NFE)

AF:

0.818

AC:

909114

AN:

1111556

Other (OTH)

AF:

0.820

AC:

49498

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

12567

25134

37700

50267

62834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20946

41892

62838

83784

104730

<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:

0.842

AC:

127925

AN:

151956

Hom.:

53955

Cov.:

AF XY:

0.840

AC XY:

62355

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.901

AC:

37372

AN:

41460

American (AMR)

AF:

0.860

AC:

13142

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.810

AC:

2810

AN:

3468

East Asian (EAS)

AF:

0.844

AC:

4324

AN:

5124

South Asian (SAS)

AF:

0.747

AC:

3604

AN:

4822

European-Finnish (FIN)

AF:

0.787

AC:

8293

AN:

10540

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.818

AC:

55582

AN:

67948

Other (OTH)

AF:

0.827

AC:

1747

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1042

2085

3127

4170

5212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.821

Hom.:

38368

Bravo

AF:

0.853

TwinsUK

AF:

0.818

AC:

3034

ALSPAC

AF:

0.826

AC:

3182

ESP6500AA

AF:

0.890

AC:

3921

ESP6500EA

AF:

0.818

AC:

7033

ExAC

AF:

0.821

AC:

99730

Asia WGS

AF:

0.809

AC:

2812

AN:

3478

EpiCase

AF:

0.814

EpiControl

AF:

0.806

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 30, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Mar 03, 2015

GeneDx

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

0.033

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.098

DEOGEN2

Benign

0.0

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.32

T;T;T

MetaRNN

Benign

6.1e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

0.90

PrimateAI

Uncertain

0.62

PROVEAN

Benign

2.2

N;N;.

REVEL

Benign

0.27

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.91

T;T;T

Vest4

0.18

ClinPred

0.0049

GERP RS

3.7

Varity_R

0.068

gMVP

0.044

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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