rs140757802

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_024753.5(TTC21B):c.2014C>T(p.Arg672Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 1.83

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14573875).

BP6

Variant 2-165915325-G-A is Benign according to our data. Variant chr2-165915325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261770.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5 link	c.2014C>T	p.Arg672Trp	missense_variant	Exon 15 of 29	ENST00000243344.8	NP_079029.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8 link	c.2014C>T	p.Arg672Trp	missense_variant	Exon 15 of 29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000123

AC:

AN:

251370

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.000112

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26132

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39686

Gnomad4 SAS exome

AF:

0.000267

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53418

Gnomad4 NFE exome

AF:

0.0000216

AC:

AN:

1111948

Gnomad4 Remaining exome

AF:

0.0000993

AC:

AN:

60394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.000394

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00125

AC:

0.00125175

AN:

0.00125175

Gnomad4 AMR

AF:

0.000393

AC:

0.000392722

AN:

0.000392722

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.00041425

AN:

0.00041425

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000204

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:1Uncertain:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Uncertain:1

Aug 04, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individual with asphyxiating thoracic dystrophy; however, additional variants in other genes were also identified (Zhang et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29068549) -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TTC21B-related disorder

Benign:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

REVEL

Benign

0.26

Sift

Benign

0.048

Sift4G

Uncertain

0.032

Polyphen

0.99

Vest4

0.56

MVP

0.47

MPC

0.089

ClinPred

0.016

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.36

Mutation Taster

=90/10

polymorphism

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