rs2064317

Positions:

chr6-35509255-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 15/20 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

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 links:

TULP1 (HGNC:):

TULP1 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=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 id is 99671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35509255-A-G is described in Lovd as [Benign]. Variant chr6-35509255-A-G is described in Lovd as [Likely_benign]. Variant chr6-35509255-A-G is described in Lovd as [Likely_pathogenic].

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/exons	MANE	Protein	UniProt
TULP1	NM_003322.6 linkuse as main transcript	c.776T>C	p.Ile259Thr	missense_variant	8/15	ENST00000229771.11	NP_003313.3	O00294-1Q0QD38
TULP1	NM_001289395.2 linkuse as main transcript	c.617T>C	p.Ile206Thr	missense_variant	7/14		NP_001276324.1	O00294-2F1T0I9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TULP1	ENST00000229771.11 linkuse as main transcript	c.776T>C	p.Ile259Thr	missense_variant	8/15	1	NM_003322.6	ENSP00000229771.6	O00294-1
TULP1	ENST00000322263.8 linkuse as main transcript	c.617T>C	p.Ile206Thr	missense_variant	7/14	1		ENSP00000319414.4	O00294-2
TULP1	ENST00000614066.4 linkuse as main transcript	c.776T>C	p.Ile259Thr	missense_variant	8/14	5		ENSP00000477534.1	A0A087WT25
TULP1	ENST00000373892.4 linkuse as main transcript	n.378T>C		non_coding_transcript_exon_variant	2/6	5

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

GnomAD3 exomes

AF:

0.381

AC:

95819

AN:

251456

Hom.:

18676

AF XY:

0.380

AC XY:

51644

AN XY:

135904

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 SAS exome

AF:

0.416

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

Gnomad4 AFR exome

AF:

0.347

Gnomad4 AMR exome

AF:

0.359

Gnomad4 ASJ exome

AF:

0.255

Gnomad4 EAS exome

AF:

0.434

Gnomad4 SAS exome

AF:

0.418

Gnomad4 FIN exome

AF:

0.388

Gnomad4 NFE exome

AF:

0.385

Gnomad4 OTH exome

AF:

0.381

GnomAD4 genome

AF:

0.369

AC:

56013

AN:

151678

Hom.:

10494

Cov.:

AF XY:

0.372

AC XY:

27569

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.346

Gnomad4 AMR

AF:

0.353

Gnomad4 ASJ

AF:

0.264

Gnomad4 EAS

AF:

0.499

Gnomad4 SAS

AF:

0.434

Gnomad4 FIN

AF:

0.384

Gnomad4 NFE

AF:

0.379

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.372

Hom.:

16584

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 03, 2015

- -

Leber congenital amaurosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Retinitis pigmentosa 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

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. -

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

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;.

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

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

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