Genetic Variant NM_017868.4:c.283C>G (chr11-113324643-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017868.4(TTC12):c.283C>G(p.Arg95Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TTC12
NM_017868.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 45
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TTC12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4 link	c.283C>G	p.Arg95Gly	missense_variant	Exon 5 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.283C>G	p.Arg95Gly	missense_variant	Exon 5 of 22	2	NM_017868.4	ENSP00000433757.1		Q9H892-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.63

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

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.8

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

PhyloP100

2.2

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.1

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

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.81

MutPred

0.40

Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);.;Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);Gain of ubiquitination at K90 (P = 0.0239);

MVP

0.86

MPC

0.47

ClinPred

1.0

GERP RS

5.1

Varity_R

0.82

gMVP

0.60

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_017868.4:c.283C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over