rs139441507

Variant summary

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

The NM_024753.5(TTC21B):c.1846C>T(p.Arg616Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00294 in 1,614,122 control chromosomes in the GnomAD database, including 33 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. R616H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 31 hom. )

Consequence

TTC21B
NM_024753.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.88

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=0.00830844).

BP6

Variant 2-165917310-G-A is Benign according to our data. Variant chr2-165917310-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, Likely_benign=2}. Variant chr2-165917310-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0028 (426/152272) while in subpopulation SAS AF= 0.0147 (71/4822). AF 95% confidence interval is 0.012. There are 2 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.1846C>T	p.Arg616Cys	missense_variant	14/29	ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.1846C>T	p.Arg616Cys	missense_variant	14/29	1	NM_024753.5	P1	Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00304

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00421

AC:

1059

AN:

251366

Hom.:

AF XY:

0.00515

AC XY:

700

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.00933

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00288

Gnomad OTH exome

AF:

0.00669

GnomAD4 exome

AF:

0.00296

AC:

4326

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

2510

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0142

Gnomad4 FIN exome

AF:

0.000505

Gnomad4 NFE exome

AF:

0.00204

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00280

AC:

426

AN:

152272

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00327

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00427

AC:

518

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TTC21B: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2013	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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 31, 2024

- -

Asphyxiating thoracic dystrophy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nephronophthisis 12

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.30

Sift

Benign

0.064

Sift4G

Uncertain

0.050

Polyphen

0.20

Vest4

0.35

MVP

0.55

MPC

0.043

ClinPred

0.094

GERP RS

4.9

Varity_R

0.30

gMVP

0.39

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