chr14-75690266-C-T

Position:

• chr14-75690266-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015072.5(TTLL5):​c.446C>T​(p.Ala149Val) variant causes a missense change. The variant allele was found at a frequency of 0.611 in 1,610,782 control chromosomes in the GnomAD database, including 314,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (22666 hom., cov: 31)
  • Exomes 𝑓: 0.62 (291833 hom.)
• Consequence: TTLL5 NM_015072.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.20

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.998419E-6).
• BP6: Variant 14-75690266-C-T is Benign according to our data. Variant chr14-75690266-C-T is described in ClinVar as [Benign]. Clinvar id is 677189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL5	NM_015072.5	c.446C>T	p.Ala149Val	missense_variant	6/32	ENST00000298832.14	NP_055887.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL5	ENST00000298832.14	c.446C>T	p.Ala149Val	missense_variant	6/32	1	NM_015072.5	ENSP00000298832.9

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74521 AN: 151932 Hom.: 22664 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.514

GnomAD3 exomes AF: 0.579 AC: 143584 AN: 248094 Hom.: 44980 AF XY: 0.585 AC XY: 78516 AN XY: 134156

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.632

Gnomad ASJ exome AF: 0.518

Gnomad EAS exome AF: 0.344

Gnomad SAS exome AF: 0.524

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.623 AC: 909252 AN: 1458732 Hom.: 291833 Cov.: 52 AF XY: 0.622 AC XY: 450958 AN XY: 725496

Gnomad4 AFR exome AF: 0.0938

Gnomad4 AMR exome AF: 0.627

Gnomad4 ASJ exome AF: 0.518

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.740

Gnomad4 NFE exome AF: 0.655

Gnomad4 OTH exome AF: 0.580

GnomAD4 genome AF: 0.490 AC: 74518 AN: 152050 Hom.: 22666 Cov.: 31 AF XY: 0.496 AC XY: 36851 AN XY: 74310

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.517

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.509

Alfa AF: 0.612 Hom.: 68877

Bravo AF: 0.465

TwinsUK AF: 0.661 AC: 2452

ALSPAC AF: 0.652 AC: 2514

ESP6500AA AF: 0.136 AC: 600

ESP6500EA AF: 0.651 AC: 5601

ExAC AF: 0.574 AC: 69700

Asia WGS AF: 0.424 AC: 1474 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.631

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone-rod dystrophy 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0000070	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	.;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.61	P;B;P
Vest4		0.095
MPC		0.11
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2303345; hg19: chr14-76156609; COSMIC: COSV54030083;