rs1048190

Positions:

• chr14-88877648-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144596.4(TTC8):​c.*238G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 345,966 control chromosomes in the GnomAD database, including 10,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3829 hom., cov: 32)
  • Exomes 𝑓: 0.25 (6330 hom.)
• Consequence: TTC8 NM_144596.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.759

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-88877648-G-A is Benign according to our data. Variant chr14-88877648-G-A is described in ClinVar as [Benign]. Clinvar id is 314807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC8	NM_144596.4	c.*238G>A		3_prime_UTR_variant	15/15	ENST00000380656.7	NP_653197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7	c.*238G>A		3_prime_UTR_variant	15/15	2	NM_144596.4	ENSP00000370031.2

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31745 AN: 152030 Hom.: 3820 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.249 AC: 48299 AN: 193818 Hom.: 6330 Cov.: 0 AF XY: 0.247 AC XY: 25403 AN XY: 102798

Gnomad4 AFR exome AF: 0.0827

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.320

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.209 AC: 31779 AN: 152148 Hom.: 3829 Cov.: 32 AF XY: 0.207 AC XY: 15412 AN XY: 74382

Gnomad4 AFR AF: 0.0926

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.190

Alfa AF: 0.221 Hom.: 841

Bravo AF: 0.201

Asia WGS AF: 0.233 AC: 810 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Bardet-Biedl syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.19

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: rs1048190; hg19: chr14-89343992;