NM_017868.4:c.217A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017868.4(TTC12):c.217A>C(p.Met73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,573,520 control chromosomes in the GnomAD database, including 184,062 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13571 hom., cov: 32)

Exomes 𝑓: 0.49 ( 170491 hom. )

Consequence

TTC12
NM_017868.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.10

Publications

49 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7309189E-4).

BP6

Variant 11-113323446-A-C is Benign according to our data. Variant chr11-113323446-A-C is described in ClinVar as [Benign]. Clinvar id is 1258984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC12	NM_017868.4 link	c.217A>C	p.Met73Leu	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.217A>C	p.Met73Leu	missense_variant	Exon 3 of 22	2	NM_017868.4	ENSP00000433757.1		Q9H892-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60535

AN:

151910

Hom.:

13575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.524

Gnomad EAS

AF:

0.418

Gnomad SAS

AF:

0.485

Gnomad FIN

AF:

0.445

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.498

Gnomad OTH

AF:

0.420

GnomAD2 exomes

AF:

0.468

AC:

104013

AN:

222224

AF XY:

0.475

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.429

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.500

Gnomad OTH exome

AF:

0.461

GnomAD4 exome

AF:

0.486

AC:

690734

AN:

1421492

Hom.:

170491

Cov.:

AF XY:

0.486

AC XY:

343907

AN XY:

707032

show subpopulations

African (AFR)

AF:

0.158

AC:

4965

AN:

31400

American (AMR)

AF:

0.496

AC:

17451

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.518

AC:

12569

AN:

24284

East Asian (EAS)

AF:

0.395

AC:

15266

AN:

38682

South Asian (SAS)

AF:

0.492

AC:

38541

AN:

78370

European-Finnish (FIN)

AF:

0.445

AC:

23295

AN:

52358

Middle Eastern (MID)

AF:

0.420

AC:

2355

AN:

5604

European-Non Finnish (NFE)

AF:

0.500

AC:

549071

AN:

1097236

Other (OTH)

AF:

0.466

AC:

27221

AN:

58366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

16557

33114

49672

66229

82786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.398

AC:

60531

AN:

152028

Hom.:

13571

Cov.:

AF XY:

0.398

AC XY:

29546

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.180

AC:

7457

AN:

41474

American (AMR)

AF:

0.442

AC:

6753

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

1814

AN:

3464

East Asian (EAS)

AF:

0.416

AC:

2149

AN:

5164

South Asian (SAS)

AF:

0.486

AC:

2336

AN:

4810

European-Finnish (FIN)

AF:

0.445

AC:

4691

AN:

10552

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.498

AC:

33828

AN:

67964

Other (OTH)

AF:

0.420

AC:

886

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1735

3470

5204

6939

8674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.468

Hom.:

80861

Bravo

AF:

0.389

TwinsUK

AF:

0.501

AC:

1859

ALSPAC

AF:

0.495

AC:

1906

ESP6500AA

AF:

0.194

AC:

852

ESP6500EA

AF:

0.505

AC:

4339

ExAC

AF:

0.461

AC:

56014

Asia WGS

AF:

0.443

AC:

1538

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Ciliary dyskinesia, primary, 45

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0010

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.0082

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

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.47

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

MetaRNN

Benign

0.00017

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;.;.;.;.;.;.;.;N;.

PhyloP100

-1.1

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.27

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.011

Sift

Benign

0.96

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

Sift4G

Benign

0.78

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

Polyphen

0.0

B;.;.;.;.;.;.;.;.;.

Vest4

0.017

MutPred

0.27

Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);.;Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);

MPC

0.067

ClinPred

0.0067

GERP RS

-8.6

Varity_R

0.052

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_017868.4:c.217A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over