rs786204090

Variant names:

• chr14-88841191-G-C
• rs753150258
• NM_144596.4:c.484G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BS1_Supporting

The NM_144596.4(TTC8):​c.484G>C​(p.Gly162Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,768 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.000016 (1 hom.)
• Consequence: TTC8 NM_144596.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.87

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000164 (24/1461768) while in subpopulation AMR AF= 0.000537 (24/44688). AF 95% confidence interval is 0.00037. There are 1 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC8	NM_144596.4	c.484G>C	p.Gly162Arg	missense_variant	Exon 5 of 15	ENST00000380656.7	NP_653197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7	c.484G>C	p.Gly162Arg	missense_variant	Exon 5 of 15	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000997 AC: 25 AN: 250742 Hom.: 1 AF XY: 0.0000885 AC XY: 12 AN XY: 135566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000725

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461768 Hom.: 1 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000537

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000642

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

TTC8-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The TTC8 c.484G>C variant is predicted to result in the amino acid substitution p.Gly162Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.072% of alleles in individuals of Latino descent in gnomAD, including 1 homozygote. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 26, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the TTC8 protein (p.Gly152Arg). This variant is present in population databases (rs753150258, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with TTC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 188127). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTC8 protein function. 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	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;T;.;.;T;T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;.;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0087	T
MutationAssessor	Benign	1.9	.;.;L;.;.;.;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.0	.;.;D;.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.056	.;.;T;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;D;D
Vest4		0.97
MutPred		0.81		.;.;Gain of MoRF binding (P = 0.0305);.;.;.;Gain of MoRF binding (P = 0.0305);.;
MVP		0.97
MPC		0.58
ClinPred		0.57	D
GERP RS		5.6
gMVP		0.91

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: rs753150258; hg19: chr14-89307535;