rs149454830

Positions:

chr2-165888322-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024753.5(TTC21B):c.3416T>C(p.Val1139Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,613,918 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. V1139I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.51

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007824808).

BP6

Variant 2-165888322-A-G is Benign according to our data. Variant chr2-165888322-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00238 (363/152320) while in subpopulation AFR AF= 0.00811 (337/41560). AF 95% confidence interval is 0.0074. There are 1 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TTC21B	NM_024753.5 linkuse as main transcript	c.3416T>C	p.Val1139Ala	missense_variant	25/29	ENST00000243344.8
TTC21B	XM_017004967.2 linkuse as main transcript	c.3416T>C	p.Val1139Ala	missense_variant	25/28
TTC21B	XM_047445870.1 linkuse as main transcript	c.2762T>C	p.Val921Ala	missense_variant	21/25
TTC21B	XM_011511871.4 linkuse as main transcript	c.2666T>C	p.Val889Ala	missense_variant	20/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.3416T>C	p.Val1139Ala	missense_variant	25/29	1	NM_024753.5	P1	Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00811

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000601

AC:

151

AN:

251138

Hom.:

AF XY:

0.000479

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00855

Gnomad AMR exome

AF:

0.000289

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:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000265

AC:

388

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.00238

AC:

363

AN:

152320

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.00275

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.3416T>C (p.V1139A) alteration is located in exon 25 (coding exon 25) of the TTC21B gene. This alteration results from a T to C substitution at nucleotide position 3416, causing the valine (V) at amino acid position 1139 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.020

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.24

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

0.27

Vest4

0.38

MVP

0.26

MPC

0.055

ClinPred

0.10

GERP RS

5.4

Varity_R

0.33

gMVP

0.47

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