Genetic Variant TTLL12:p.Phe542Leu (chr22-43169518-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_015140.4(TTLL12):c.1626T>G(p.Phe542Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,605,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTLL12
NM_015140.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.437

Variant links:

Genes affected

TTLL12 (HGNC:28974): (tubulin tyrosine ligase like 12) Enables H4K20me3 modified histone binding activity and tubulin binding activity. Involved in negative regulation of type I interferon-mediated signaling pathway and regulation of mitotic cell cycle. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TTLL12 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=0.025835186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTLL12	NM_015140.4 link	c.1626T>G	p.Phe542Leu	missense_variant	Exon 12 of 14	ENST00000216129.7	NP_055955.1	Q14166A0A024R4U3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTLL12	ENST00000216129.7 link	c.1626T>G	p.Phe542Leu	missense_variant	Exon 12 of 14	1	NM_015140.4	ENSP00000216129.6	Q14166
TTLL12	ENST00000494035.1 link	c.-112T>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	2		ENSP00000476297.1	V9GY16
TTLL12	ENST00000494035.1 link	c.-112T>G		5_prime_UTR_variant	Exon 2 of 4	2		ENSP00000476297.1	V9GY16
TTLL12	ENST00000484711.1 link	n.757T>G		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000207

AC:

AN:

246318

Hom.:

AF XY:

0.000195

AC XY:

AN XY:

133454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00154

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.000207

Gnomad OTH exome

AF:

0.000668

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1453650

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

722026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000274

Gnomad4 ASJ exome

AF:

0.00209

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.0000565

Gnomad4 NFE exome

AF:

0.0000632

Gnomad4 OTH exome

AF:

0.000250

GnomAD4 genome

AF:

0.000138

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1626T>G (p.F542L) alteration is located in exon 12 (coding exon 12) of the TTLL12 gene. This alteration results from a T to G substitution at nucleotide position 1626, causing the phenylalanine (F) at amino acid position 542 to be replaced by a leucine (L). 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

0.78

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.015

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.84

M_CAP

Benign

0.0099

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.060

Sift

Benign

0.30

Sift4G

Benign

0.64

Polyphen

0.0090

Vest4

0.49

MutPred

0.50

Gain of catalytic residue at F542 (P = 0.0025);

MVP

0.18

MPC

0.12

ClinPred

0.031

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.078

gMVP

0.62

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