17-48769132-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130918.3(TTLL6):c.2533C>A(p.Leu845Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTLL6 NM_001130918.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.884

Genes affected

TTLL6 (HGNC:26664): (tubulin tyrosine ligase like 6) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to act upstream of or within microtubule bundle formation; microtubule severing; and positive regulation of cilium movement. Located in ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3416091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTLL6	NM_001130918.3	c.2533C>A	p.Leu845Met	missense_variant	15/16	ENST00000393382.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL6	ENST00000393382.8	c.2533C>A	p.Leu845Met	missense_variant	15/16	2	NM_001130918.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251150 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.2533C>A (p.L845M) alteration is located in exon 15 (coding exon 15) of the TTLL6 gene. This alteration results from a C to A substitution at nucleotide position 2533, causing the leucine (L) at amino acid position 845 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
REVEL	Benign	0.16
Sift4G	Pathogenic	0.0	D;D
Vest4		0.34
MVP		0.23
MPC		0.70
ClinPred		0.74	D
GERP RS		4.8
gMVP		0.073

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

Publications

LitVar

Other links and lift over

dbSNP: rs1160917452; hg19: chr17-46846494;