Variant 22-43059392-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012263.5(TTLL1):c.883G>T(p.Ala295Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000707 in 1,612,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TTLL1
NM_012263.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.07

Variant links:

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 links:

TTLL1 (HGNC:):

TTLL1 links:

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ACMG classification

Classification made for transcript

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=0.06860179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL1	NM_012263.5 linkuse as main transcript	c.883G>T	p.Ala295Ser	missense_variant	8/11	ENST00000266254.12	NP_036395.1	O95922-1A0A024R4U6
TTLL1	NR_027779.2 linkuse as main transcript	n.1191G>T		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTLL1	ENST00000266254.12 linkuse as main transcript	c.883G>T	p.Ala295Ser	missense_variant	8/11	1	NM_012263.5	ENSP00000266254.7		O95922-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

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

GnomAD3 exomes

AF:

0.0000763

AC:

AN:

248978

Hom.:

AF XY:

0.0000668

AC XY:

AN XY:

134632

show subpopulations

Gnomad AFR exome

AF:

0.000995

Gnomad AMR exome

AF:

0.0000585

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:

0.000165

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459680

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726086

show subpopulations

Gnomad4 AFR exome

AF:

0.00138

Gnomad4 AMR exome

AF:

0.0000675

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000361

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00132

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

Alfa

AF:

0.0000652

Hom.:

Bravo

AF:

0.000378

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.883G>T (p.A295S) alteration is located in exon 8 (coding exon 6) of the TTLL1 gene. This alteration results from a G to T substitution at nucleotide position 883, causing the alanine (A) at amino acid position 295 to be replaced by a serine (S). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

T;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.46

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.22

Sift

Benign

0.23

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.097

B;B

Vest4

0.51

MVP

0.19

MPC

0.56

ClinPred

0.030

GERP RS

5.3

Varity_R

0.13

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over