rs587777471

Positions:

• chr14-75863694-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015072.5(TTLL5):​c.3354G>A​(p.Trp1118Ter) 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 139515.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-75863694-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTLL5	NM_015072.5	c.3354G>A	p.Trp1118Ter	stop_gained	29/32	ENST00000298832.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL5	ENST00000298832.14	c.3354G>A	p.Trp1118Ter	stop_gained	29/32	1	NM_015072.5	P4
TTLL5	ENST00000557636.5	c.3399G>A	p.Trp1133Ter	stop_gained	30/32	1		A2
TTLL5	ENST00000556893.5	c.2007G>A	p.Trp669Ter	stop_gained	15/17	1
TTLL5	ENST00000554510.5	c.1881G>A	p.Trp627Ter	stop_gained	14/16	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2014

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.25
GERP RS		5.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777471; hg19: chr14-76330037;