rs150880478

chr14-88840883-A-G

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.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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 4.99

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 (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: {Benign=5, Likely_benign=2, 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 GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC8	NM_144596.4	c.284A>G	p.Lys95Arg	missense_variant	4/15	ENST00000380656.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC8	ENST00000380656.7	c.284A>G	p.Lys95Arg	missense_variant	4/15	2	NM_144596.4

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152198 Hom.: 5 Cov.: 32

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.: 13 AF XY: 0.00634 AC XY: 861 AN XY: 135788

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.: 71 Cov.: 32 AF XY: 0.00530 AC XY: 3855 AN XY: 727172

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.: 5 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74490

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.: 4

Bravo AF: 0.00300

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00592 AC: 719

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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

Bardet-Biedl syndrome 8 Uncertain:1 Benign: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:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	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

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TTC8: BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
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	D
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	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	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	T
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

Other links and lift over

dbSNP: rs150880478; hg19: chr14-89307227;