rs79037278

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024753.5(TTC21B):c.2322+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,607,380 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 44 hom. )

Consequence

TTC21B
NM_024753.5 splice_donor_region, intron

Scores

Splicing: ADA: 0.0004591

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.85

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-165912511-T-C is Benign according to our data. Variant chr2-165912511-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165912511-T-C is described in Lovd as [Benign]. Variant chr2-165912511-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00578 (880/152300) while in subpopulation EAS AF= 0.0243 (126/5178). AF 95% confidence interval is 0.0209. There are 5 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5 linkuse as main transcript	c.2322+3A>G		splice_donor_region_variant, intron_variant		ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8 linkuse as main transcript	c.2322+3A>G		splice_donor_region_variant, intron_variant		1	NM_024753.5	P1	Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.00581

AC:

884

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0247

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00595

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00732

AC:

1840

AN:

251380

Hom.:

AF XY:

0.00688

AC XY:

935

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.0266

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.00583

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.00653

AC:

9497

AN:

1455080

Hom.:

Cov.:

AF XY:

0.00634

AC XY:

4596

AN XY:

724436

show subpopulations

Gnomad4 AFR exome

AF:

0.000690

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.0223

Gnomad4 SAS exome

AF:

0.00182

Gnomad4 FIN exome

AF:

0.0223

Gnomad4 NFE exome

AF:

0.00611

Gnomad4 OTH exome

AF:

0.00589

GnomAD4 genome

AF:

0.00578

AC:

880

AN:

152300

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

474

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.0243

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0240

Gnomad4 NFE

AF:

0.00595

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00567

Hom.:

Bravo

AF:

0.00430

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TTC21B: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	This variant is associated with the following publications: (PMID: 21258341, 31180159) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 23, 2015	- -

Nephronophthisis 12

Benign:2

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Asphyxiating thoracic dystrophy 4

Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Joubert syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00046

dbscSNV1_RF

Benign

0.030

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