14-88824780-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144596.4(TTC8):c.73G>T(p.Asp25Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC8 NM_144596.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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	c.73G>T	p.Asp25Tyr	missense_variant	1/15	ENST00000380656.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC8	ENST00000380656.7	c.73G>T	p.Asp25Tyr	missense_variant	1/15	2	NM_144596.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461098 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1435354). This variant has not been reported in the literature in individuals affected with TTC8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 25 of the TTC8 protein (p.Asp25Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;.;T;T;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;.;D;.;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.075	D
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D;D
Polyphen		0.69, 0.43, 1.0	.;.;P;.;.;.;B;P;D
Vest4		0.77
MutPred		0.36		Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);Gain of MoRF binding (P = 0.0636);
MVP		0.93
MPC		0.59
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.64

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

Other links and lift over

dbSNP: rs772967779; hg19: chr14-89291124;