chr2-165941046-T-A

Position:

chr2-165941046-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_024753.5(TTC21B):c.691A>T(p.Thr231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,962 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 11 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 1.70

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:

TTC21B-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

TTC21B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035384238).

BP6

Variant 2-165941046-T-A is Benign according to our data. Variant chr2-165941046-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198257.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.691A>T	p.Thr231Ser	missense_variant	6/29	ENST00000243344.8
TTC21B-AS1	NR_038983.1 linkuse as main transcript	n.277-6151T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.691A>T	p.Thr231Ser	missense_variant	6/29	1	NM_024753.5	P1	Q7Z4L5-1
TTC21B-AS1	ENST00000440322.5 linkuse as main transcript	n.221-6151T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00105

AC:

264

AN:

251318

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00116

AC:

1695

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

826

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.000748

AC:

114

AN:

152336

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000977

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00112

AC:

136

EpiCase

AF:

0.00185

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	This variant is associated with the following publications: (PMID: 26940125, 21258341, 27884173, 30037327) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 16, 2018	The c.691A>T; p.Thr231Ser variant has been reported in the heterozygous state in 8 patients diagnosed with a range of ciliopathies, including Jeune asphyxiating thoracic dystrophy (JATD), Meckel-Gruber Syndrome (MKS), Bardet-Biedl syndrome (BBS - 4 individuals), and nephronophthisis (NPHP - 2 individuals) (Davis 2011). The results of functional studies in zebrafish embryos and human cell lines resulted in this variant being classified as a hypomorphic allele (Davis 2011). It is classified as a variant of unknown significance in ClinVar (ID: 198257). However, this variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.1% (identified on 280 out of 277,060 chromosomes, including 2 homozygotes), and was found in the Saudi Human Genome Program with a population frequency of 1.5% (identified on 53 out of 3504 chromosomes, including 2 homozygotes) (Abouelhoda 2016). This variant was also reported in a patient with Alport syndrome who also carried two pathogenic variants in the COL4A3 gene (Bullich 2017). The threonine at position 231 is moderately conserved, considering 11 species, and computational analyses of the effects of the p.Thr231Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Although population frequencies argue against pathogenicity, the clinical significance of the p.Thr231Ser variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTC21B: BP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 17, 2017

- -

Asphyxiating thoracic dystrophy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nephronophthisis 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Joubert syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

TTC21B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2022

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

0.20

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.22

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

M_CAP

Benign

0.021

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

REVEL

Benign

0.21

Sift

Benign

0.057

Sift4G

Benign

0.082

Polyphen

0.63

Vest4

0.76

MVP

0.34

MPC

0.057

ClinPred

0.025

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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