rs114557412

chr14-88839501-A-Gchr14-88839501-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_144596.4(TTC8):c.194A>G(p.Asp65Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,613,350 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D65N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (7 hom.)
• Consequence: TTC8 NM_144596.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 8.83

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012029707).
• BP6: Variant 14-88839501-A-G is Benign according to our data. Variant chr14-88839501-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262515.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=3, Likely_benign=1}. Variant chr14-88839501-A-G is described in Lovd as [Benign]. Variant chr14-88839501-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00323 (492/152282) while in subpopulation AFR AF= 0.0113 (471/41566). AF 95% confidence interval is 0.0105. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC8	NM_144596.4	c.194A>G	p.Asp65Gly	missense_variant	3/15	ENST00000380656.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC8	ENST00000380656.7	c.194A>G	p.Asp65Gly	missense_variant	3/15	2	NM_144596.4

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000860 AC: 216 AN: 251200 Hom.: 1 AF XY: 0.000597 AC XY: 81 AN XY: 135776

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000372 AC: 543 AN: 1461068 Hom.: 7 Cov.: 30 AF XY: 0.000323 AC XY: 235 AN XY: 726860

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74470

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00147 Hom.: 1

Bravo AF: 0.00372

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 8 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 17, 2021	- -
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. -
Uncertain significance, criteria provided, single submitter	research	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	Sep 17, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2017	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, 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, 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. -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;D;.;.;T;D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.;.;D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;D;D
Vest4		0.84
MVP		0.58
MPC		0.60
ClinPred		0.092	T
GERP RS		6.0
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114557412; hg19: chr14-89305845;