Variant 14-88824709-T-C 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>C(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 0.00000619 in 1,454,278 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TTC8
NM_144596.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter 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:

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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	UniProt
TTC8	NM_144596.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/15	ENST00000380656.7

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000858

AC:

AN:

232976

Hom.:

AF XY:

0.00000785

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:

0.000116

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:

0.00000619

AC:

AN:

1454278

Hom.:

Cov.:

AF XY:

0.00000553

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:

0.000228

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Invitae

Feb 26, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with TTC8-related conditions. This variant is present in population databases (rs776086794, ExAC 0.03%). This sequence change affects the initiator methionine of the TTC8 mRNA. The next in-frame methionine is located at codon 5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Uncertain

0.060

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.068

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

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.98

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

MetaSVM

Benign

-0.39

MutationTaster

Benign

0.96

D;D;D;D;D;N

PROVEAN

Uncertain

-3.6

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

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.042

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

Polyphen

0.37, 0.13, 0.0070

.;.;B;.;.;.;B;B;B

Vest4

0.63

MutPred

0.99

Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);Gain of phosphorylation at M1 (P = 0.0395);

MVP

0.88

ClinPred

0.96

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.43

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