22-43063902-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_012263.5(TTLL1):c.658C>T(p.Arg220Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,802 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TTLL1 NM_012263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

Genes affected

TTLL1 (HGNC:1312): (TTL family tubulin polyglutamylase complex subunit L1) 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 several processes, including cerebellar Purkinje cell differentiation; mucociliary clearance; and regulation of blastocyst development. Predicted to be located in cytoplasm; extracellular region; and microtubule cytoskeleton. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity TTLL1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTLL1	NM_012263.5	c.658C>T	p.Arg220Trp	missense_variant	7/11	ENST00000266254.12
TTLL1	NR_027779.2	n.966C>T		non_coding_transcript_exon_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL1	ENST00000266254.12	c.658C>T	p.Arg220Trp	missense_variant	7/11	1	NM_012263.5	P1
TTLL1	ENST00000331018.8	c.658C>T	p.Arg220Trp	missense_variant	5/8	1
TTLL1	ENST00000439248.5	c.*582C>T		3_prime_UTR_variant, NMD_transcript_variant	8/12	1
TTLL1	ENST00000440761.1	c.*550C>T		3_prime_UTR_variant, NMD_transcript_variant	8/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251366 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727200

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Oct 06, 2023

The c.658C>T (p.R220W) alteration is located in exon 7 (coding exon 5) of the TTLL1 gene. This alteration results from a C to T substitution at nucleotide position 658, causing the arginine (R) at amino acid position 220 to be replaced by a tryptophan (W). 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	4.9	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.89		Loss of phosphorylation at T223 (P = 0.0545);Loss of phosphorylation at T223 (P = 0.0545);
MVP		0.72
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.83
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1279755974; hg19: chr22-43459908; COSMIC: COSV56741056;