Genetic Variant TTC21B:c.*878A>G (chr2-165873877-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024753.5(TTC21B):c.*878A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,138 control chromosomes in the GnomAD database, including 1,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1063 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTC21B
NM_024753.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.376

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=-0.85).

BP6

Variant 2-165873877-T-C is Benign according to our data. Variant chr2-165873877-T-C is described in ClinVar as [Benign]. Clinvar id is 331801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TTC21B	NM_024753.5 link	c.*878A>G	3_prime_UTR_variant	Exon 29 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_047445870.1 link	c.*878A>G	3_prime_UTR_variant	Exon 25 of 25		XP_047301826.1
TTC21B	XM_011511871.4 link	c.*878A>G	3_prime_UTR_variant	Exon 24 of 24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344 link	c.*878A>G		3_prime_UTR_variant	Exon 29 of 29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

AF:

0.111

AC:

16935

AN:

152020

Hom.:

1065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0873

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.111

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

Gnomad4 NFE exome

AF:

0.00

GnomAD4 genome

AF:

0.111

AC:

16933

AN:

152138

Hom.:

1063

Cov.:

AF XY:

0.113

AC XY:

8419

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0599

Gnomad4 AMR

AF:

0.0872

Gnomad4 ASJ

AF:

0.230

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.153

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.123

Hom.:

154

Bravo

AF:

0.105

Asia WGS

AF:

0.124

AC:

429

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nephronophthisis 12

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.0

DANN

Benign

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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