14-88824708-A-G

Variant names:

• chr14-88824708-A-G
• rs747906724
• NM_144596.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PVS1_Supporting

The NM_144596.4(TTC8):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000179 in 1,454,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TTC8 NM_144596.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.64
• Publications: 3 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, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 51

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 5 codons. Genomic position: 88824720. Lost 0.008 part of the original CDS.

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.1A>G	p.Met1?	start_lost	Exon 1 of 15	NP_653197.2
	TTC8	NM_001288781.1		c.1A>G	p.Met1?	start_lost	Exon 2 of 16	NP_001275710.1	Q86U25
	TTC8	NM_198309.3		c.1A>G	p.Met1?	start_lost	Exon 2 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.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000370031.2	Q8TAM2-4
	TTC8	ENST00000338104.10	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000337653.6	A0A0C4DGX9
	TTC8	ENST00000622513.4	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENSP00000482721.1	A0A0C4DGY3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000172 AC: 4 AN: 232340 AF XY: 0.00000787

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.000209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000965

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1454000 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 722598

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.0000228 AC: 1 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.000386 AC: 10 AN: 25924

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 84926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5358

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108858

Other (OTH) AF: 0.0000833 AC: 5 AN: 60056

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome (1)
-	1	-	Bardet-Biedl syndrome 8;C3150715:Retinitis pigmentosa 51 (1)
-	1	-	TTC8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.71	T
PhyloP100		3.6
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.67
MutPred		1.0		Loss of disorder (P = 0.1433)
MVP		0.80
ClinPred		0.95	D
GERP RS		3.1
PromoterAI		-0.57	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.42
Mutation Taster		=94/106	disease causing

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: rs747906724; hg19: chr14-89291052;