14-88840976-T-C

Variant names:

• chr14-88840976-T-C
• rs17700296
• NM_144596.4:c.329+48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144596.4(TTC8):​c.329+48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,606 control chromosomes in the GnomAD database, including 45,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3374 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42229 hom.)
• Consequence: TTC8 NM_144596.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.552
• Publications: 9 publications found

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]

TTC8 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 51

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-88840976-T-C is Benign according to our data. Variant chr14-88840976-T-C is described in ClinVar as Benign. ClinVar VariationId is 262516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC8	NM_144596.4	c.329+48T>C		intron_variant	Intron 4 of 14	ENST00000380656.7	NP_653197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7	c.329+48T>C		intron_variant	Intron 4 of 14	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30046 AN: 152040 Hom.: 3366 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.212 AC: 53296 AN: 251174 AF XY: 0.211

Gnomad AFR exome AF: 0.0974

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.236 AC: 345386 AN: 1461448 Hom.: 42229 Cov.: 33 AF XY: 0.234 AC XY: 170360 AN XY: 727042

African (AFR) AF: 0.0876 AC: 2933 AN: 33470

American (AMR) AF: 0.171 AC: 7664 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5671 AN: 26132

East Asian (EAS) AF: 0.316 AC: 12553 AN: 39688

South Asian (SAS) AF: 0.159 AC: 13703 AN: 86252

European-Finnish (FIN) AF: 0.217 AC: 11582 AN: 53416

Middle Eastern (MID) AF: 0.128 AC: 738 AN: 5768

European-Non Finnish (NFE) AF: 0.249 AC: 276809 AN: 1111636

Other (OTH) AF: 0.227 AC: 13733 AN: 60384

GnomAD4 genome AF: 0.198 AC: 30077 AN: 152158 Hom.: 3374 Cov.: 32 AF XY: 0.195 AC XY: 14474 AN XY: 74402

African (AFR) AF: 0.0971 AC: 4033 AN: 41524

American (AMR) AF: 0.197 AC: 3006 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3470

East Asian (EAS) AF: 0.318 AC: 1649 AN: 5180

South Asian (SAS) AF: 0.178 AC: 859 AN: 4814

European-Finnish (FIN) AF: 0.214 AC: 2264 AN: 10604

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16836 AN: 67976

Other (OTH) AF: 0.177 AC: 373 AN: 2110

Alfa AF: 0.217 Hom.: 1091

Bravo AF: 0.193

Asia WGS AF: 0.221 AC: 768 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.52
DANN	Benign	0.70
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17700296; hg19: chr14-89307320; COSMIC: COSV57626195; COSMIC: COSV57626195;