chr14-75863694-G-A

Variant names:

• chr14-75863694-G-A
• rs587777471
• NM_015072.5:c.3354G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015072.5(TTLL5):​c.3354G>A​(p.Trp1118*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,459,796 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTLL5 NM_015072.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.73
• Publications: 2 publications found

Genes affected

TTLL5 (HGNC:19963): (tubulin tyrosine ligase like 5) This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.[provided by RefSeq, Feb 2010]

TTLL5 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 19

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75863694-G-A is Pathogenic according to our data. Variant chr14-75863694-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 139515.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015072.5. 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
	TTLL5	NM_015072.5	MANE Select	c.3354G>A	p.Trp1118*	stop_gained	Exon 29 of 32	NP_055887.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL5	ENST00000298832.14	TSL:1 MANE Select	c.3354G>A	p.Trp1118*	stop_gained	Exon 29 of 32	ENSP00000298832.9
	TTLL5	ENST00000557636.5	TSL:1	c.3399G>A	p.Trp1133*	stop_gained	Exon 30 of 32	ENSP00000450713.1
	TTLL5	ENST00000556893.5	TSL:1	c.2007G>A	p.Trp669*	stop_gained	Exon 15 of 17	ENSP00000452524.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459796 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726140

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111098

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cone-rod dystrophy 19 Pathogenic:1

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.7
Vest4		0.25
GERP RS		5.8
Mutation Taster		=27/173	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587777471; hg19: chr14-76330037;