NM_144596.4:c.1327C>T

Variant names:

• chr14-88872432-C-T
• rs140698625
• NM_144596.4:c.1327C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_144596.4(TTC8):​c.1327C>T​(p.Arg443Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,830 control chromosomes in the GnomAD database, including 2 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. R443Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: TTC8 NM_144596.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 2.42
• Publications: 7 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076960176).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000617 (94/152246) while in subpopulation NFE AF = 0.000956 (65/68024). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD 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.1327C>T	p.Arg443Trp	missense	Exon 13 of 15	NP_653197.2
	TTC8	NM_001288781.1		c.1375C>T	p.Arg459Trp	missense	Exon 14 of 16	NP_001275710.1	Q86U25
	TTC8	NM_198309.3		c.1297C>T	p.Arg433Trp	missense	Exon 13 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.1327C>T	p.Arg443Trp	missense	Exon 13 of 15	ENSP00000370031.2	Q8TAM2-4
	TTC8	ENST00000338104.10	TSL:1	c.1375C>T	p.Arg459Trp	missense	Exon 13 of 15	ENSP00000337653.6	A0A0C4DGX9
	TTC8	ENST00000622513.4	TSL:1	c.1297C>T	p.Arg433Trp	missense	Exon 12 of 14	ENSP00000482721.1	A0A0C4DGY3

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000724 AC: 182 AN: 251272 AF XY: 0.000781

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00109 AC: 1590 AN: 1461584 Hom.: 2 Cov.: 31 AF XY: 0.00106 AC XY: 773 AN XY: 727110

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.000403 AC: 18 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00128 AC: 1425 AN: 1111832

Other (OTH) AF: 0.000795 AC: 48 AN: 60380

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74436

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Bardet-Biedl syndrome 8 (2)
-	1	-	Bardet-Biedl syndrome (1)
-	1	-	Bardet-Biedl syndrome 8;C3150715:Retinitis pigmentosa 51 (1)
-	-	1	Inborn genetic diseases (1)
1	-	-	Macular dystrophy (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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.077	T
MetaSVM	Uncertain	0.28	D
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.76
MPC		0.11
ClinPred		0.61	D
GERP RS		4.7
gMVP		0.59
Mutation Taster		=28/72	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: rs140698625; hg19: chr14-89338776;