14-88877326-G-C

Variant names:

• chr14-88877326-G-C
• rs142073418
• NM_144596.4:c.1464G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000380656.7(TTC8):​c.1464G>C​(p.Ala488Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,613,502 control chromosomes in the GnomAD database, including 32 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. A488A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (31 hom.)
• Consequence: TTC8 ENST00000380656.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.0970
• 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 51

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.003).
• BP6: Variant 14-88877326-G-C is Benign according to our data. Variant chr14-88877326-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215548.
• BP7: Synonymous conserved (PhyloP=-0.097 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0032 (486/152082) while in subpopulation SAS AF = 0.0054 (26/4812). AF 95% confidence interval is 0.00396. There are 1 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380656.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC8	NM_144596.4	MANE Select	c.1464G>C	p.Ala488Ala	synonymous	Exon 15 of 15	NP_653197.2
	TTC8	NM_001288781.1		c.1512G>C	p.Ala504Ala	synonymous	Exon 16 of 16	NP_001275710.1
	TTC8	NM_198309.3		c.1434G>C	p.Ala478Ala	synonymous	Exon 15 of 15	NP_938051.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC8	ENST00000380656.7	TSL:2 MANE Select	c.1464G>C	p.Ala488Ala	synonymous	Exon 15 of 15	ENSP00000370031.2
	TTC8	ENST00000338104.10	TSL:1	c.1512G>C	p.Ala504Ala	synonymous	Exon 15 of 15	ENSP00000337653.6
	TTC8	ENST00000622513.4	TSL:1	c.1434G>C	p.Ala478Ala	synonymous	Exon 14 of 14	ENSP00000482721.1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 486 AN: 151964 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00442 AC: 1108 AN: 250616 AF XY: 0.00481

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00517

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00447 AC: 6538 AN: 1461420 Hom.: 31 Cov.: 31 AF XY: 0.00464 AC XY: 3372 AN XY: 727002

African (AFR) AF: 0.000448 AC: 15 AN: 33462

American (AMR) AF: 0.000447 AC: 20 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00749 AC: 646 AN: 86246

European-Finnish (FIN) AF: 0.0106 AC: 566 AN: 53396

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00458 AC: 5090 AN: 1111728

Other (OTH) AF: 0.00316 AC: 191 AN: 60374

GnomAD4 genome AF: 0.00320 AC: 486 AN: 152082 Hom.: 1 Cov.: 33 AF XY: 0.00330 AC XY: 245 AN XY: 74322

African (AFR) AF: 0.000892 AC: 37 AN: 41492

American (AMR) AF: 0.000393 AC: 6 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4812

European-Finnish (FIN) AF: 0.0109 AC: 115 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00268 Hom.: 2

Bravo AF: 0.00231

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00403

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 8 (1)
-	-	1	Retinal dystrophy (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.3
DANN	Benign	0.60
PhyloP100		-0.097
Mutation Taster		=99/1	polymorphism

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: rs142073418; hg19: chr14-89343670;