NM_003322.6:c.1376T>A

Variant names:

• chr6-35500100-A-T
• rs121909075
• NM_003322.6:c.1376T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_003322.6(TULP1):​c.1376T>A​(p.Ile459Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47

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]

LOC124901309 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 5) in uniprot entity TULP1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003322.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 6-35500100-A-T is Pathogenic according to our data. Variant chr6-35500100-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7359.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-35500100-A-T is described in Lovd as [Likely_pathogenic]. Variant chr6-35500100-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TULP1	NM_003322.6	c.1376T>A	p.Ile459Lys	missense_variant	Exon 14 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.1217T>A	p.Ile406Lys	missense_variant	Exon 13 of 14		NP_001276324.1
LOC124901309	XR_007059561.1	n.75+1893A>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.1376T>A	p.Ile459Lys	missense_variant	Exon 14 of 15	1	NM_003322.6	ENSP00000229771.6
TULP1	ENST00000322263.8	c.1217T>A	p.Ile406Lys	missense_variant	Exon 13 of 14	1		ENSP00000319414.4
TULP1	ENST00000614066.4	c.1370T>A	p.Ile457Lys	missense_variant	Exon 13 of 14	5		ENSP00000477534.1
TULP1	ENST00000495781.1	n.552T>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 14 Pathogenic:1

Feb 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 459 of the TULP1 protein (p.Ile459Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy and/or TULP1-related conditions (PMID: 9462750, 31429209). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7359). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TULP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TULP1 function (PMID: 26427415, 26987071). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.88	.;D;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	D;D;.
REVEL	Pathogenic	0.93
Sift	Benign	0.035	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.41	B;B;.
Vest4		0.87
MutPred		0.85		.;Gain of helix (P = 6e-04);.;
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.81

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

Other links and lift over

dbSNP: rs121909075; hg19: chr6-35467877;