chr14-88824709-T-A

Variant names:

• chr14-88824709-T-A
• NM_144596.4:c.2T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97

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 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	c.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 15	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	19
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	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;.;D;.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
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	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.60

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: chr14-89291053;