rs7764472

Positions:

• chr6-35511797-G-C
• chr6-35511797-G-T

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.200C>G​(p.Thr67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.853 in 1,557,490 control chromosomes in the GnomAD database, including 568,033 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59522 hom., cov: 30)
  • Exomes 𝑓: 0.85 (508511 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.430

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.4844005E-7).
• BP6: Variant 6-35511797-G-C is Benign according to our data. Variant chr6-35511797-G-C is described in ClinVar as [Benign]. Clinvar id is 286865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35511797-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TULP1	NM_003322.6	c.200C>G	p.Thr67Arg	missense_variant	4/15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.190+383C>G		intron_variant			NP_001276324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.200C>G	p.Thr67Arg	missense_variant	4/15	1	NM_003322.6	ENSP00000229771.6

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134066 AN: 151878 Hom.: 59457 Cov.: 30

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.861

GnomAD3 exomes AF: 0.851 AC: 142773 AN: 167774 Hom.: 60980 AF XY: 0.844 AC XY: 76863 AN XY: 91076

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.915

Gnomad ASJ exome AF: 0.807

Gnomad EAS exome AF: 0.843

Gnomad SAS exome AF: 0.775

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.853

Gnomad OTH exome AF: 0.848

GnomAD4 exome AF: 0.850 AC: 1194417 AN: 1405494 Hom.: 508511 Cov.: 64 AF XY: 0.847 AC XY: 587026 AN XY: 693450

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.911

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.853

Gnomad4 SAS exome AF: 0.779

Gnomad4 FIN exome AF: 0.817

Gnomad4 NFE exome AF: 0.852

Gnomad4 OTH exome AF: 0.849

GnomAD4 genome AF: 0.883 AC: 134195 AN: 151996 Hom.: 59522 Cov.: 30 AF XY: 0.880 AC XY: 65357 AN XY: 74282

Gnomad4 AFR AF: 0.974

Gnomad4 AMR AF: 0.890

Gnomad4 ASJ AF: 0.817

Gnomad4 EAS AF: 0.848

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.820

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.860

Alfa AF: 0.853 Hom.: 41451

Bravo AF: 0.896

TwinsUK AF: 0.854 AC: 3167

ALSPAC AF: 0.859 AC: 3311

ESP6500AA AF: 0.969 AC: 4097

ESP6500EA AF: 0.864 AC: 7196

ExAC AF: 0.826 AC: 89812

Asia WGS AF: 0.826 AC: 2870 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	- -

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	- -

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	0.039
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.5
DANN	Benign	0.19
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00046	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	6.5e-7	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.5	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.48	N;.
REVEL	Benign	0.18
Sift	Benign	0.90	T;.
Sift4G	Benign	0.68	T;T
Polyphen		0.0	B;.
Vest4		0.079
MPC		0.30
ClinPred		0.00041	T
GERP RS		0.72
Varity_R		0.039
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs7764472; hg19: chr6-35479574; COSMIC: COSV57692003;