Variant 2-218738668-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014640.5(TTLL4):c.992C>G(p.Thr331Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000034 ( 0 hom. )

Consequence

TTLL4
NM_014640.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.602

Variant links:

Genes affected

TTLL4 (HGNC:28976): (tubulin tyrosine ligase like 4) 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 regulation of blastocyst development. Predicted to be located in cytosol. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052909672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL4	NM_014640.5 linkuse as main transcript	c.992C>G	p.Thr331Ser	missense_variant	3/20	ENST00000392102.6	NP_055455.3	Q14679A0A024R424

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TTLL4	ENST00000392102.6 linkuse as main transcript	c.992C>G	p.Thr331Ser	missense_variant	3/20	1	NM_014640.5	ENSP00000375951.1	Q14679
TTLL4	ENST00000258398.8 linkuse as main transcript	c.992C>G	p.Thr331Ser	missense_variant	1/18	2		ENSP00000258398.4	Q14679
TTLL4	ENST00000442769.5 linkuse as main transcript	c.992C>G	p.Thr331Ser	missense_variant	3/19	5		ENSP00000396555.1	E7EX20
TTLL4	ENST00000457313.5 linkuse as main transcript	c.497C>G	p.Thr166Ser	missense_variant	2/19	2		ENSP00000393332.1	E9PH58

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Feb 21, 2024

The c.992C>G (p.T331S) alteration is located in exon 3 (coding exon 1) of the TTLL4 gene. This alteration results from a C to G substitution at nucleotide position 992, causing the threonine (T) at amino acid position 331 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

Benign

0.075

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.9

DANN

Benign

0.43

DEOGEN2

Benign

0.0051

.;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.56

T;.;T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.053

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

.;L;.;L

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.080

N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.58

T;T;T;T

Sift4G

Benign

0.71

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.072

MutPred

0.13

.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.16

MPC

0.17

ClinPred

0.032

GERP RS

2.7

Varity_R

0.034

gMVP

0.064

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over