rs150880478

Positions:

chr14-88840883-A-G

Variant summary

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

The NM_144596.4(TTC8):c.284A>G(p.Lys95Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00454 in 1,614,074 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 71 hom. )

Consequence

TTC8
NM_144596.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 4.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007837504).

BP6

Variant 14-88840883-A-G is Benign according to our data. Variant chr14-88840883-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196600.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=2}. Variant chr14-88840883-A-G is described in Lovd as [Benign]. Variant chr14-88840883-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00351 (534/152316) while in subpopulation SAS AF= 0.0263 (127/4824). AF 95% confidence interval is 0.0226. There are 5 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC8	NM_144596.4 linkuse as main transcript	c.284A>G	p.Lys95Arg	missense_variant	4/15	ENST00000380656.7	NP_653197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC8	ENST00000380656.7 linkuse as main transcript	c.284A>G	p.Lys95Arg	missense_variant	4/15	2	NM_144596.4	ENSP00000370031		Q8TAM2-4

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00537

AC:

1349

AN:

251238

Hom.:

AF XY:

0.00634

AC XY:

861

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00465

AC:

6799

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

3855

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00351

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0232

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00375

Gnomad4 OTH exome

AF:

0.00498

GnomAD4 genome

AF:

0.00351

AC:

534

AN:

152316

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0263

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00416

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00592

AC:

719

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Bardet-Biedl syndrome 8

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -

Bardet-Biedl syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP	Oct 01, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TTC8: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.041

T;T;.;.;T;T;.;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;D;T;T;.;.;.;D

MetaRNN

Benign

0.0078

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.63

.;.;N;.;.;.;N;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.35

.;.;.;.;N;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.57

.;.;.;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0030, 0.0050

.;.;B;.;.;.;B;B

Vest4

0.13

MVP

0.82

MPC

0.47

ClinPred

0.043

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.33

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

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