dbSNP rs776086794: TTC8:p.Met1? (chr14-88824709-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_144596.4(TTC8):c.2T>A(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 0.00000206 in 1,454,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TTC8
NM_144596.4 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.97

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa 51
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TTC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 88824720. Lost 0.008 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC8	NM_144596.4 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 15	ENST00000380656.7	NP_653197.2	Q8TAM2-4Q86U25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 15	2	NM_144596.4	ENSP00000370031.2		Q8TAM2-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454278

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.00

AC:

AN:

43932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108938

Other (OTH)

AF:

0.00

AC:

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.077

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

Eigen

Benign

-0.084

Eigen_PC

Benign

0.0068

FATHMM_MKL

Uncertain

0.78

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

-0.43

PhyloP100

3.0

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

0.024

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

Polyphen

0.74, 0.13, 0.0070

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

Vest4

0.81

MutPred

0.99

Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);Gain of ubiquitination at M1 (P = 0.0109);

MVP

0.90

ClinPred

1.0

GERP RS

4.4

PromoterAI

-0.68

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.60

Mutation Taster

=60/140

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over