rs2064317

chr6-35509255-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.854

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]

ACMG classification

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	UniProt
TULP1	NM_003322.6	c.776T>C	p.Ile259Thr	missense_variant	8/15	ENST00000229771.11
TULP1	NM_001289395.2	c.617T>C	p.Ile206Thr	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TULP1	ENST00000229771.11	c.776T>C	p.Ile259Thr	missense_variant	8/15	1	NM_003322.6	P4
TULP1	ENST00000322263.8	c.617T>C	p.Ile206Thr	missense_variant	7/14	1		A2
TULP1	ENST00000614066.4	c.776T>C	p.Ile259Thr	missense_variant	8/14	5		A2
TULP1	ENST00000373892.4	n.378T>C		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55979 AN: 151560 Hom.: 10488 Cov.: 31

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

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.: 60 AF XY: 0.382 AC XY: 278027 AN XY: 726976

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.: 31 AF XY: 0.372 AC XY: 27569 AN XY: 74094

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

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

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	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	6.1
Dann	Benign	0.13
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.18	T;T;T
MetaRNN	Benign	0.00068	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs2064317; hg19: chr6-35477032; COSMIC: COSV57692162; COSMIC: COSV57692162;