Genetic Variant TTC12:p.Leu45Arg (chr11-113323363-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017868.4(TTC12):c.134T>G(p.Leu45Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TTC12
NM_017868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

Variant links:

Genes affected

TTC12 (HGNC:23700): (tetratricopeptide repeat domain 12) Involved in axonemal dynein complex assembly and sperm axoneme assembly. Located in centrosome and cytoplasm. Implicated in primary ciliary dyskinesia 45. [provided by Alliance of Genome Resources, Apr 2022]

TTC12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3760871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4 link	c.134T>G	p.Leu45Arg	missense_variant	Exon 3 of 22	ENST00000529221.6	NP_060338.3	Q9H892-1A8K8G6Q53G14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC12	ENST00000529221.6 link	c.134T>G	p.Leu45Arg	missense_variant	Exon 3 of 22	2	NM_017868.4	ENSP00000433757.1		Q9H892-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250850

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135592

show subpopulations

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:

0.0000233

AC:

AN:

1461270

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726956

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:

0.0000288

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134T>G (p.L45R) alteration is located in exon 3 (coding exon 2) of the TTC12 gene. This alteration results from a T to G substitution at nucleotide position 134, causing the leucine (L) at amino acid position 45 to be replaced by an arginine (R). 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

0.46

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

T;T;T;.;.;.;T;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.38

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.;.;.;M;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

N;D;N;N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.;.;.

Vest4

0.43

MutPred

0.26

Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);.;Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);Loss of stability (P = 0.0178);

MVP

0.88

MPC

0.50

ClinPred

0.95

GERP RS

5.2

Varity_R

0.55

gMVP

0.60

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