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GeneBe

14-88824715-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144596.4(TTC8):​c.8C>T​(p.Ser3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TTC8
NM_144596.4 missense

Scores

1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.496
Variant links:
Genes affected
TTC8 (HGNC:20087): (tetratricopeptide repeat domain 8) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is involved in the formation of cilia. A mutation in this gene has also been implicated in nonsyndromic retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06439084).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTC8NM_144596.4 linkuse as main transcriptc.8C>T p.Ser3Leu missense_variant 1/15 ENST00000380656.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTC8ENST00000380656.7 linkuse as main transcriptc.8C>T p.Ser3Leu missense_variant 1/152 NM_144596.4 Q8TAM2-4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000425
AC:
1
AN:
235514
Hom.:
0
AF XY:
0.00000777
AC XY:
1
AN XY:
128730
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000950
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1455674
Hom.:
0
Cov.:
31
AF XY:
0.00000553
AC XY:
4
AN XY:
723628
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 04, 2021This variant is present in population databases (rs752229926, ExAC 0.003%). This sequence change replaces serine with leucine at codon 3 of the TTC8 protein (p.Ser3Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant has not been reported in the literature in individuals affected with TTC8-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.078
T;T;.;.;T;T;.;.;.
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.66
T;T;T;T;.;.;T;.;T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.064
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.41
T
Sift4G
Benign
0.40
T;T;T;T;T;T;T;T;T
Polyphen
0.018, 0.0, 0.0020
.;.;B;.;.;.;B;B;B
Vest4
0.080
MutPred
0.26
Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);
MVP
0.65
MPC
0.11
ClinPred
0.11
T
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
gMVP
0.14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752229926; hg19: chr14-89291059; API