Variant 14-88824709-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_144596.4(TTC8):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,606,386 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 Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TTC8
NM_144596.4 start_lost

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.97

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]

TTC8 links:

TTC8 (HGNC:):

TTC8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC8	NM_144596.4 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/15	ENST00000380656.7	NP_653197.2	Q8TAM2-4Q86U25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/15	2	NM_144596.4	ENSP00000370031.2		Q8TAM2-4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000429

AC:

AN:

232976

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127434

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:

0.00000961

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1454278

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000812

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TTC8-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2024

The TTC8 c.2T>G variant is predicted to disrupt the translation initiation site (Start Loss). To our knowledge, this variant, or other start-loss variants, have not been reported in the literature in patients with TTC8-related disorders. This variant is reported in 0.0017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, an additional methionine residue resides four amino acids downstream. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.079

T;T;.;.;T;T;.;.;.

Eigen

Benign

-0.054

Eigen_PC

Benign

0.027

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

D;D;D;D;.;.;D;.;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.37

MutationTaster

Benign

0.96

D;D;D;D;D;N

PROVEAN

Uncertain

-4.2

D;.;N;.;N;N;N;N;N

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;.;D;.;D;D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;D;D;D;T;D;D

Polyphen

0.74, 0.23, 0.036

.;.;P;.;.;.;B;P;B

Vest4

0.82

MutPred

1.0

Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);

MVP

0.90

ClinPred

1.0

GERP RS

4.4

gMVP

0.59

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over