rs755412340

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_144596.4(TTC8):​c.1051C>T​(p.Arg351Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000118 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TTC8
NM_144596.4 missense, splice_region

Scores

11
5
1
Splicing: ADA: 0.9715
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTC8NM_144596.4 linkc.1051C>T p.Arg351Trp missense_variant, splice_region_variant Exon 12 of 15 ENST00000380656.7 NP_653197.2 Q8TAM2-4Q86U25

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTC8ENST00000380656.7 linkc.1051C>T p.Arg351Trp missense_variant, splice_region_variant Exon 12 of 15 2 NM_144596.4 ENSP00000370031.2 Q8TAM2-4

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151946
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250898
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135630
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461448
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151946
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74182
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 8 Uncertain:1
Oct 24, 2022
New York Genome Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Bardet-Biedl syndrome 8;C3150715:Retinitis pigmentosa 51 Uncertain:1
May 21, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

TTC8-related disorder Uncertain:1
Sep 17, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The TTC8 c.1051C>T variant is predicted to result in the amino acid substitution p.Arg351Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1
Feb 03, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The R341W variant in the TTC8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R341W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R341W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R341W as a variant of uncertain significance. -

Bardet-Biedl syndrome Uncertain:1
Sep 01, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine with tryptophan at codon 341 of the TTC8 protein (p.Arg341Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs755412340, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with TTC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 423070). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
35
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.55
D;D;T;.;.;D;D;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;.;.;D;.
M_CAP
Uncertain
0.095
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.19
T
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-7.9
.;.;D;.;.;D;D;D;D
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
.;.;D;.;.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;.;.;.;D;D
Vest4
0.80
MVP
0.79
MPC
0.54
ClinPred
1.0
D
GERP RS
4.8
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.97
dbscSNV1_RF
Pathogenic
0.72
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: rs755412340; hg19: chr14-89337894; COSMIC: COSV57625880; API