rs7592429

Variant names:

Variant summary

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

The NM_024753.5(TTC21B):c.826A>G(p.Thr276Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,613,484 control chromosomes in the GnomAD database, including 793,953 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T276T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.95 ( 69687 hom., cov: 31)

Exomes 𝑓: 1.0 ( 724266 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.74

Publications

37 publications found

Variant links:

Genes affected

TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]

TTC21B Gene-Disease associations (from GenCC):

nephronophthisis 12
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
asphyxiating thoracic dystrophy 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TTC21B 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=7.554098E-7).

BP6

Variant 2-165931826-T-C is Benign according to our data. Variant chr2-165931826-T-C is described in ClinVar as Benign. ClinVar VariationId is 130660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 8 of 29	NP_079029.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 8 of 29	ENSP00000243344.7
TTC21B	ENST00000464374.5	TSL:1	n.866A>G		non_coding_transcript_exon	Exon 8 of 11
TTC21B	ENST00000679840.1		c.826A>G	p.Thr276Ala	missense	Exon 8 of 27	ENSP00000505248.1

Frequencies

GnomAD3 genomes

AF:

0.955

AC:

145177

AN:

152056

Hom.:

69645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.843

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.982

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.969

GnomAD2 exomes

AF:

0.988

AC:

248335

AN:

251268

AF XY:

0.992

show subpopulations

Gnomad AFR exome

AF:

0.842

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.993

GnomAD4 exome

AF:

0.995

AC:

1454466

AN:

1461310

Hom.:

724266

Cov.:

AF XY:

0.996

AC XY:

724066

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.839

AC:

28069

AN:

33442

American (AMR)

AF:

0.991

AC:

44290

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26125

AN:

26126

East Asian (EAS)

AF:

1.00

AC:

39672

AN:

39672

South Asian (SAS)

AF:

1.00

AC:

86219

AN:

86242

European-Finnish (FIN)

AF:

1.00

AC:

53397

AN:

53398

Middle Eastern (MID)

AF:

0.990

AC:

5708

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111257

AN:

1111598

Other (OTH)

AF:

0.989

AC:

59729

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

305

609

914

1218

1523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21658

43316

64974

86632

108290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.955

AC:

145276

AN:

152174

Hom.:

69687

Cov.:

AF XY:

0.956

AC XY:

71152

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.843

AC:

34985

AN:

41490

American (AMR)

AF:

0.982

AC:

14978

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5176

AN:

5176

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4828

European-Finnish (FIN)

AF:

1.00

AC:

10624

AN:

10624

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67966

AN:

68014

Other (OTH)

AF:

0.969

AC:

2047

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

294

588

883

1177

1471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.983

Hom.:

208145

Bravo

AF:

0.948

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.840

AC:

3700

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.985

AC:

119611

Asia WGS

AF:

0.990

AC:

3444

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Asphyxiating thoracic dystrophy 4 (2)

Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)

Nephronophthisis 12 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.6

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.043

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.032

MetaRNN

Benign

7.6e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.4

PhyloP100

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

2.3

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.014

MPC

0.030

ClinPred

0.0028

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.064

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over