rs1553506530

chr2-165888353-AAT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_024753.5(TTC21B):c.3383_3384del(p.Tyr1128LeufsTer10) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC21B NM_024753.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-165888353-AAT-A is Pathogenic according to our data. Variant chr2-165888353-AAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 528906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.3383_3384del	p.Tyr1128LeufsTer10	frameshift_variant	25/29	ENST00000243344.8
TTC21B	XM_011511871.4	c.2633_2634del	p.Tyr878LeufsTer10	frameshift_variant	20/24
TTC21B	XM_017004967.2	c.3383_3384del	p.Tyr1128LeufsTer10	frameshift_variant	25/28
TTC21B	XM_047445870.1	c.2729_2730del	p.Tyr910LeufsTer10	frameshift_variant	21/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.3383_3384del	p.Tyr1128LeufsTer10	frameshift_variant	25/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy;C0687120:Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 528906). This variant has not been reported in the literature in individuals affected with TTC21B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1128Leufs*10) in the TTC21B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC21B are known to be pathogenic (PMID: 18327258, 21068128, 21258341, 23559409, 24876116, 25492405, 27491411, 29068549). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1553506530; hg19: chr2-166744863;