rs199882533
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS2_Supporting
The NM_015072.5(TTLL5):c.1627G>A(p.Glu543Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,614,128 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 3 hom. )
Consequence
TTLL5
NM_015072.5 missense
NM_015072.5 missense
Scores
6
6
5
Clinical Significance
Conservation
PhyloP100: 6.08
Genes affected
TTLL5 (HGNC:19963): (tubulin tyrosine ligase like 5) This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.[provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
?
Variant 14-75764691-G-A is Pathogenic according to our data. Variant chr14-75764691-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 139517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75764691-G-A is described in Lovd as [Likely_pathogenic].
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTLL5 | NM_015072.5 | c.1627G>A | p.Glu543Lys | missense_variant | 19/32 | ENST00000298832.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTLL5 | ENST00000298832.14 | c.1627G>A | p.Glu543Lys | missense_variant | 19/32 | 1 | NM_015072.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000243 AC: 61AN: 251186Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135724
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GnomAD4 exome AF: 0.000137 AC: 200AN: 1461834Hom.: 3 Cov.: 30 AF XY: 0.000161 AC XY: 117AN XY: 727222
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74466
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 543 of the TTLL5 protein (p.Glu543Lys). This variant is present in population databases (rs199882533, gnomAD 0.06%). This missense change has been observed in individuals with retinal dystrophy (PMID: 24791901, 28173158). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 139517). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTLL5 protein function. Experimental studies have shown that this missense change affects TTLL5 function (PMID: 27162334). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Cone-rod dystrophy 19 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 09, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;D;D
Polyphen
D;D;D;.
Vest4
MVP
MPC
0.51
ClinPred
T
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