chr6-35503816-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003322.6(TULP1):āc.1145T>Cā(p.Phe382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,460,054 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 Pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.000011 ( 0 hom. )
Consequence
TULP1
NM_003322.6 missense
NM_003322.6 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 4.18
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003322.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 6-35503816-A-G is Pathogenic according to our data. Variant chr6-35503816-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35503816-A-G is described in Lovd as [Likely_pathogenic]. Variant chr6-35503816-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TULP1 | NM_003322.6 | c.1145T>C | p.Phe382Ser | missense_variant | 12/15 | ENST00000229771.11 | |
LOC124901309 | XR_007059561.1 | n.76-4411A>G | intron_variant, non_coding_transcript_variant | ||||
TULP1 | NM_001289395.2 | c.986T>C | p.Phe329Ser | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TULP1 | ENST00000229771.11 | c.1145T>C | p.Phe382Ser | missense_variant | 12/15 | 1 | NM_003322.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248518Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134602
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460054Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726354
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 14 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 382 of the TULP1 protein (p.Phe382Ser). This variant is present in population databases (rs121909076, gnomAD 0.006%). This missense change has been observed in individuals with retinitis pigmentosa and Leber congenital amaurosis (PMID: 15557452, 25324289, 32901917, 33090715, 33946315). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Phe329Ser. ClinVar contains an entry for this variant (Variation ID: 7362). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
0.97
.;Gain of disorder (P = 0.0057);.;
MVP
MPC
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at