14-88824741-T-G

Variant names:

• chr14-88824741-T-G
• NM_144596.4:c.34T>G

Variant summary

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

The NM_144596.4(TTC8):​c.34T>G​(p.Trp12Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC8 NM_144596.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 rank	MANE	Protein	UniProt
TTC8	NM_144596.4	c.34T>G	p.Trp12Gly	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.34T>G	p.Trp12Gly	missense_variant	Exon 1 of 15	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome Uncertain:1

Jul 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TTC8-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with glycine at codon 12 of the TTC8 protein (p.Trp12Gly). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.19	T;T;.;.;T;T;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.9	.;.;M;.;.;.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	.;.;N;.;N;N;N;N;D
REVEL	Benign	0.26
Sift	Benign	0.16	.;.;T;.;T;T;D;T;T
Sift4G	Benign	0.090	T;T;T;T;T;T;T;T;T
Polyphen		0.069, 0.74, 0.43	.;.;B;.;.;.;P;B;B
Vest4		0.70
MutPred		0.70		Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);Gain of disorder (P = 0.0034);
MVP		0.86
MPC		0.69
ClinPred		0.95	D
GERP RS		5.5
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-89291085;