rs2303345

Variant names:

• chr14-75690266-C-T
• rs2303345
• NM_015072.5:c.446C>T
• TTLL5 p.Ala149Val

Your query was ambiguous. Multiple possible variants found:

• chr14-75690266-C-T
• chr14-75690266-C-A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 47 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• TTLL5-related retinopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL5	NM_015072.5	MANE Select	c.446C>T	p.Ala149Val	missense	Exon 6 of 32	NP_055887.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL5	ENST00000298832.14	TSL:1 MANE Select	c.446C>T	p.Ala149Val	missense	Exon 6 of 32	ENSP00000298832.9	Q6EMB2-1
	TTLL5	ENST00000557636.5	TSL:1	c.446C>T	p.Ala149Val	missense	Exon 6 of 32	ENSP00000450713.1	G3V2J9
	TTLL5	ENST00000882579.1		c.446C>T	p.Ala149Val	missense	Exon 6 of 32	ENSP00000552638.1

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

GnomAD2 exomes AF: 0.579 AC: 143584 AN: 248094 AF XY: 0.585

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 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

African (AFR) AF: 0.0938 AC: 3136 AN: 33416

American (AMR) AF: 0.627 AC: 27614 AN: 44066

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13509 AN: 26094

East Asian (EAS) AF: 0.394 AC: 15561 AN: 39524

South Asian (SAS) AF: 0.526 AC: 44961 AN: 85540

European-Finnish (FIN) AF: 0.740 AC: 39507 AN: 53382

Middle Eastern (MID) AF: 0.450 AC: 2590 AN: 5756

European-Non Finnish (NFE) AF: 0.655 AC: 727392 AN: 1110666

Other (OTH) AF: 0.580 AC: 34982 AN: 60288

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

African (AFR) AF: 0.122 AC: 5070 AN: 41496

American (AMR) AF: 0.584 AC: 8928 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1791 AN: 3464

East Asian (EAS) AF: 0.366 AC: 1891 AN: 5164

South Asian (SAS) AF: 0.522 AC: 2512 AN: 4814

European-Finnish (FIN) AF: 0.752 AC: 7938 AN: 10560

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.655 AC: 44527 AN: 67956

Other (OTH) AF: 0.509 AC: 1075 AN: 2112

Alfa AF: 0.601 Hom.: 90274

Bravo AF: 0.465

Asia WGS AF: 0.424 AC: 1474 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.631

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cone-rod dystrophy 19 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
PhyloP100		5.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.056
Sift	Benign	0.63	T
Sift4G	Benign	0.57	T
Varity_R		0.11
gMVP		0.30
Mutation Taster		=96/4	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2303345;

hg19: chr14-76156609;

COSMIC: COSV54030083;