chr14-88852966-C-T

Variant names:

• chr14-88852966-C-T
• rs137853922
• NM_144596.4:c.625-5C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_144596.4(TTC8):​c.625-5C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0002747
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7 O:1
• Conservation: PhyloP100: 0.492
• 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 -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 VariationId is 100608.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

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.625-5C>T		splice_region intron	N/A	NP_653197.2
	TTC8	NM_001288781.1		c.673-5C>T		splice_region intron	N/A	NP_001275710.1	Q86U25
	TTC8	NM_198309.3		c.595-5C>T		splice_region 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.625-5C>T		splice_region intron	N/A	ENSP00000370031.2	Q8TAM2-4
	TTC8	ENST00000338104.10	TSL:1	c.673-5C>T		splice_region intron	N/A	ENSP00000337653.6	A0A0C4DGX9
	TTC8	ENST00000622513.4	TSL:1	c.595-5C>T		splice_region intron	N/A	ENSP00000482721.1	A0A0C4DGY3

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1213 AN: 152116 Hom.: 9 Cov.: 32

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

GnomAD2 exomes AF: 0.00870 AC: 2181 AN: 250700 AF XY: 0.00911

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 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.: 30 AF XY: 0.0122 AC XY: 8864 AN XY: 726298

African (AFR) AF: 0.00159 AC: 53 AN: 33418

American (AMR) AF: 0.00414 AC: 185 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 747 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00599 AC: 516 AN: 86202

European-Finnish (FIN) AF: 0.00248 AC: 132 AN: 53326

Middle Eastern (MID) AF: 0.0160 AC: 92 AN: 5758

European-Non Finnish (NFE) AF: 0.0140 AC: 15577 AN: 1110338

Other (OTH) AF: 0.0117 AC: 707 AN: 60270

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152234 Hom.: 9 Cov.: 32 AF XY: 0.00764 AC XY: 569 AN XY: 74430

African (AFR) AF: 0.00234 AC: 97 AN: 41536

American (AMR) AF: 0.00458 AC: 70 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10598

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 839 AN: 68022

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00848

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0137

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	Bardet-Biedl syndrome 8 (2)
-	2	-	Retinitis pigmentosa (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		0.49
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs137853922; hg19: chr14-89319310;