chr6-35509248-C-G

Position:

chr6-35509248-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_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. 14/20 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. K261T) has been classified as Likely pathogenic.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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 id is 94127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35509248-C-G is described in Lovd as [Likely_benign]. Variant chr6-35509248-C-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
TULP1	NM_003322.6 linkuse as main transcript	c.783G>C	p.Lys261Asn	missense_variant	8/15	ENST00000229771.11
TULP1	NM_001289395.2 linkuse as main transcript	c.624G>C	p.Lys208Asn	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TULP1	ENST00000229771.11 linkuse as main transcript	c.783G>C	p.Lys261Asn	missense_variant	8/15	1	NM_003322.6	P4	O00294-1
TULP1	ENST00000322263.8 linkuse as main transcript	c.624G>C	p.Lys208Asn	missense_variant	7/14	1		A2	O00294-2
TULP1	ENST00000614066.4 linkuse as main transcript	c.783G>C	p.Lys261Asn	missense_variant	8/14	5		A2
TULP1	ENST00000373892.4 linkuse as main transcript	n.385G>C		non_coding_transcript_exon_variant	2/6	5

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

GnomAD3 exomes

AF:

0.823

AC:

206899

AN:

251466

Hom.:

85485

AF XY:

0.815

AC XY:

110700

AN XY:

135910

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 SAS exome

AF:

0.753

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

Gnomad4 AFR exome

AF:

0.904

Gnomad4 AMR exome

AF:

0.895

Gnomad4 ASJ exome

AF:

0.802

Gnomad4 EAS exome

AF:

0.850

Gnomad4 SAS exome

AF:

0.758

Gnomad4 FIN exome

AF:

0.784

Gnomad4 NFE exome

AF:

0.818

Gnomad4 OTH exome

AF:

0.820

GnomAD4 genome

AF:

0.842

AC:

127925

AN:

151956

Hom.:

53955

Cov.:

AF XY:

0.840

AC XY:

62355

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.901

Gnomad4 AMR

AF:

0.860

Gnomad4 ASJ

AF:

0.810

Gnomad4 EAS

AF:

0.844

Gnomad4 SAS

AF:

0.747

Gnomad4 FIN

AF:

0.787

Gnomad4 NFE

AF:

0.818

Gnomad4 OTH

AF:

0.827

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	GeneDx	Mar 03, 2015	- -

Leber congenital amaurosis 15

Benign:2

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

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

0.033

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.098

DEOGEN2

Benign

0.041

.;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

-2.2

.;N;.

MutationTaster

Benign

0.99

P;P

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

Polyphen

0.0

B;B;.

Vest4

0.18

MutPred

0.071

.;Loss of methylation at K261 (P = 0.0032);Loss of methylation at K261 (P = 0.0032);

MPC

0.31

ClinPred

0.0049

GERP RS

3.7

Varity_R

0.068

gMVP

0.044

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

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