rs114064158

Variant names:

• chr14-88875079-G-A
• rs114064158
• NM_144596.4:c.1401G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-88875079-G-A
• chr14-88875079-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_144596.4(TTC8):​c.1401G>A​(p.Pro467Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000599 in 1,612,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P467P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: TTC8 NM_144596.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -3.04
• Publications: 0 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 (REVEL=0.077).
• BP6: Variant 14-88875079-G-A is Benign according to our data. Variant chr14-88875079-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262513.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00294 (447/151892) while in subpopulation AFR AF = 0.00999 (414/41440). AF 95% confidence interval is 0.0092. There are 1 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1401G>A	p.Pro467Pro	synonymous	Exon 14 of 15	NP_653197.2
	TTC8	NM_001288781.1		c.1449G>A	p.Pro483Pro	synonymous	Exon 15 of 16	NP_001275710.1	Q86U25
	TTC8	NM_198309.3		c.1371G>A	p.Pro457Pro	synonymous	Exon 14 of 15	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.1401G>A	p.Pro467Pro	synonymous	Exon 14 of 15	ENSP00000370031.2	Q8TAM2-4
	TTC8	ENST00000338104.10	TSL:1	c.1449G>A	p.Pro483Pro	synonymous	Exon 14 of 15	ENSP00000337653.6	A0A0C4DGX9
	TTC8	ENST00000622513.4	TSL:1	c.1371G>A	p.Pro457Pro	synonymous	Exon 13 of 14	ENSP00000482721.1	A0A0C4DGY3

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 151776 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000882 AC: 221 AN: 250620 AF XY: 0.000650

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1460348 Hom.: 2 Cov.: 30 AF XY: 0.000295 AC XY: 214 AN XY: 726540

African (AFR) AF: 0.0106 AC: 353 AN: 33446

American (AMR) AF: 0.000738 AC: 33 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26106

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39562

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52920

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111362

Other (OTH) AF: 0.000779 AC: 47 AN: 60316

GnomAD4 genome AF: 0.00294 AC: 447 AN: 151892 Hom.: 1 Cov.: 32 AF XY: 0.00260 AC XY: 193 AN XY: 74254

African (AFR) AF: 0.00999 AC: 414 AN: 41440

American (AMR) AF: 0.00131 AC: 20 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67938

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00359

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 8 (1)
-	-	1	not specified (1)
-	1	-	Retinitis pigmentosa (1)
-	-	1	TTC8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114064158; hg19: chr14-89341423; COSMIC: COSV100581533;