6-35506041-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_003322.6(TULP1):āc.961T>Gā(p.Tyr321Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,618 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y321C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003322.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TULP1 | NM_003322.6 | c.961T>G | p.Tyr321Asp | missense_variant | 10/15 | ENST00000229771.11 | |
LOC124901309 | XR_007059561.1 | n.76-2186A>C | intron_variant, non_coding_transcript_variant | ||||
TULP1 | NM_001289395.2 | c.802T>G | p.Tyr268Asp | missense_variant | 9/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TULP1 | ENST00000229771.11 | c.961T>G | p.Tyr321Asp | missense_variant | 10/15 | 1 | NM_003322.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251134Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135804
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461618Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727110
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 321 of the TULP1 protein (p.Tyr321Asp). This variant is present in population databases (rs794726991, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Leber congenital amaurosis (PMID: 23847139). 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: 193654). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 25, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at