rs137853922

Positions:

• chr14-88852966-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_144596.4(TTC8):​c.625-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,611,916 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (136 hom.)
• Consequence: TTC8 NM_144596.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002747
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7 O:1
• Conservation: PhyloP100: 0.492

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 14-88852966-C-T is Benign according to our data. Variant chr14-88852966-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100608.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Benign=3, Likely_benign=1}. Variant chr14-88852966-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00797 (1214/152234) while in subpopulation NFE AF= 0.0123 (839/68022). AF 95% confidence interval is 0.0116. There are 9 homozygotes in gnomad4. There are 569 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC8	NM_144596.4	c.625-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000380656.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC8	ENST00000380656.7	c.625-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_144596.4

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1213 AN: 152116 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00870 AC: 2181 AN: 250700 Hom.: 19 AF XY: 0.00911 AC XY: 1235 AN XY: 135504

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00647

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0123 AC: 18009 AN: 1459682 Hom.: 136 Cov.: 30 AF XY: 0.0122 AC XY: 8864 AN XY: 726298

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00599

Gnomad4 FIN exome AF: 0.00248

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152234 Hom.: 9 Cov.: 32 AF XY: 0.00764 AC XY: 569 AN XY: 74430

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0120 Hom.: 4

Bravo AF: 0.00848

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Retinitis pigmentosa Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Bardet-Biedl syndrome 8 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TTC8: BP4, BS1, BS2 -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.018
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: rs137853922; hg19: chr14-89319310;