chr14-88852966-C-T

Position:

chr14-88852966-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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:3B:7O:1

Conservation

PhyloP100: 0.492

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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: {not_provided=1, Likely_benign=1, Uncertain_significance=2, Benign=3}. 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 linkuse as main transcript	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 linkuse as main transcript	c.625-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_144596.4		Q8TAM2-4

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1213

AN:

152116

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00911

AC XY:

1235

AN XY:

135504

show subpopulations

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.:

AF XY:

0.0122

AC XY:

8864

AN XY:

726298

show subpopulations

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.:

Cov.:

AF XY:

0.00764

AC XY:

569

AN XY:

74430

show subpopulations

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.:

Bravo

AF:

0.00848

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0139

EpiControl

AF:

0.0137

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

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:1Benign: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:1Other: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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over