rs141980901

Variant names:

• chr6-35499990-C-T
• rs141980901
• NM_003322.6:c.1486G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_003322.6(TULP1):​c.1486G>A​(p.Ala496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A496V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6 O:1
• Conservation: PhyloP100: -0.0830
• Publications: 7 publications found

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

ENSG00000228559 (HGNC:58100):

LOC124901309 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003322.6
• 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=0.00881651).
• BP6: Variant 6-35499990-C-T is Benign according to our data. Variant chr6-35499990-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99664.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6	c.1486G>A	p.Ala496Thr	missense_variant	Exon 14 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.1327G>A	p.Ala443Thr	missense_variant	Exon 13 of 14		NP_001276324.1
LOC124901309	XR_007059561.1	n.75+1783C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.1486G>A	p.Ala496Thr	missense_variant	Exon 14 of 15	1	NM_003322.6	ENSP00000229771.6

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000860 AC: 216 AN: 251230 AF XY: 0.000861

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000674 AC: 985 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.000649 AC XY: 472 AN XY: 727204

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.000560 AC: 623 AN: 1112004

Other (OTH) AF: 0.00177 AC: 107 AN: 60396

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74450

African (AFR) AF: 0.00111 AC: 46 AN: 41552

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68002

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Jan 24, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TULP1 c.1486G>A (p.Ala496Thr) results in a non-conservative amino acid change located in the Tubby, C-terminal domain (IPR000007) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 251230 control chromosomes, predominantly at a frequency of 0.0027 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1486G>A has been reported in the literature as a heterozygous variant in at-least one in individual affected with Leber Congenital Amaurosis, who had an alternate molecular basis of disease described below (example, El Shamieh_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. The co-occurrence with another reported pathogenic RP1 gene variant is, homozygous c.2391_2392delAA, p.Asp799*, in the proband from a consanguineous family, providing supporting evidence for a benign role (El Shamieh_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.

Leber congenital amaurosis 15 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Retinitis pigmentosa Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

TULP1-related disorder Benign:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0	.;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;L;.
PhyloP100		-0.083
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.83	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.37	T;T;.
Sift4G	Benign	0.53	T;T;T
Vest4		0.36
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141980901; hg19: chr6-35467767;