22-43046471-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012263.5(TTLL1):c.1081A>G(p.Ile361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TTLL1 NM_012263.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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]

TTLL1-AS1 (HGNC:40111): (TTLL1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10189295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTLL1	NM_012263.5	c.1081A>G	p.Ile361Val	missense_variant	10/11	ENST00000266254.12
TTLL1-AS1	NR_125362.1	n.1771+5170T>C		intron_variant, non_coding_transcript_variant
TTLL1	NR_027779.2	n.1389A>G		non_coding_transcript_exon_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTLL1	ENST00000266254.12	c.1081A>G	p.Ile361Val	missense_variant	10/11	1	NM_012263.5	P1
TTLL1-AS1	ENST00000443063.1	n.1771+5170T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74266

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH 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

Apr 07, 2022

The c.1081A>G (p.I361V) alteration is located in exon 10 (coding exon 8) of the TTLL1 gene. This alteration results from a A to G substitution at nucleotide position 1081, causing the isoleucine (I) at amino acid position 361 to be replaced by a valine (V). 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	Benign	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	14
Dann	Benign	0.60
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.64	N;.
MutationTaster	Benign	0.76	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.16
Sift	Benign	0.65	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;B
Vest4		0.38
MutPred		0.40		Gain of disorder (P = 0.1489);.;
MVP		0.030
MPC		0.36
ClinPred		0.15	T
GERP RS		2.2
Varity_R		0.033
gMVP		0.38

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: rs1601654308; hg19: chr22-43442477;