rs17700521

Variant names:

• chr14-88849531-C-G
• rs17700521
• NM_144596.4:c.625-3440C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144596.4(TTC8):​c.625-3440C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 151,880 control chromosomes in the GnomAD database, including 3,828 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3828 hom., cov: 32)
• Consequence: TTC8 NM_144596.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 51

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• TTC8-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144596.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC8	NM_144596.4	MANE Select	c.625-3440C>G		intron	N/A	NP_653197.2
	TTC8	NM_001288781.1		c.672+2856C>G		intron	N/A	NP_001275710.1	Q86U25
	TTC8	NM_198309.3		c.595-3440C>G		intron	N/A	NP_938051.1	A0A0C4DGY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC8	ENST00000380656.7	TSL:2 MANE Select	c.625-3440C>G		intron	N/A	ENSP00000370031.2	Q8TAM2-4
	TTC8	ENST00000338104.10	TSL:1	c.672+2856C>G		intron	N/A	ENSP00000337653.6	A0A0C4DGX9
	TTC8	ENST00000622513.4	TSL:1	c.595-3440C>G		intron	N/A	ENSP00000482721.1	A0A0C4DGY3

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31708 AN: 151764 Hom.: 3820 Cov.: 32

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.192

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.209 AC: 31740 AN: 151880 Hom.: 3828 Cov.: 32 AF XY: 0.207 AC XY: 15386 AN XY: 74214

African (AFR) AF: 0.0931 AC: 3859 AN: 41458

American (AMR) AF: 0.203 AC: 3102 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 768 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1647 AN: 5162

South Asian (SAS) AF: 0.223 AC: 1073 AN: 4806

European-Finnish (FIN) AF: 0.243 AC: 2549 AN: 10494

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.266 AC: 18038 AN: 67934

Other (OTH) AF: 0.190 AC: 400 AN: 2108

Alfa AF: 0.233 Hom.: 545

Bravo AF: 0.200

Asia WGS AF: 0.235 AC: 815 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17700521; hg19: chr14-89315875;