14-88824715-C-T

Variant names:

• chr14-88824715-C-T
• rs752229926
• NM_144596.4:c.8C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001288782.1(TTC8):​c.-555C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTC8 NM_001288782.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.496

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06439084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC8	NM_144596.4	c.8C>T	p.Ser3Leu	missense_variant	Exon 1 of 15	ENST00000380656.7	NP_653197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7	c.8C>T	p.Ser3Leu	missense_variant	Exon 1 of 15	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235514 Hom.: 0 AF XY: 0.00000777 AC XY: 1 AN XY: 128730

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: 0.00000950

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455674 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723628

Gnomad4 AFR exome AF: 0.0000300

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 8;C3150715:Retinitis pigmentosa 51 Uncertain:1

Dec 27, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Uncertain:1

Jul 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces serine with leucine at codon 3 of the TTC8 protein (p.Ser3Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs752229926, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with TTC8-related conditions. 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	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;.;.;T;T;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.66	T;T;T;T;.;.;T;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.064	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.23	.;.;N;.;.;.;N;N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	.;.;N;.;N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.27	.;.;T;.;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T
Polyphen		0.018, 0.0, 0.0020	.;.;B;.;.;.;B;B;B
Vest4		0.080
MutPred		0.26		Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);Loss of phosphorylation at S3 (P = 0.0132);
MVP		0.65
MPC		0.11
ClinPred		0.11	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.14

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: rs752229926; hg19: chr14-89291059;