rs115504901

Positions:

• chr2-165883959-A-C
• chr2-165883959-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024753.5(TTC21B):​c.3519T>G​(p.Thr1173Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,060 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1173T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: TTC21B NM_024753.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -1.29

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-165883959-A-C is Benign according to our data. Variant chr2-165883959-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261781.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=3}. Variant chr2-165883959-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00259 (395/152252) while in subpopulation AMR AF= 0.00458 (70/15290). AF 95% confidence interval is 0.00372. There are 2 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.3519T>G	p.Thr1173Thr	synonymous_variant	26/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.3519T>G	p.Thr1173Thr	synonymous_variant	26/28		XP_016860456.1
TTC21B	XM_047445870.1	c.2865T>G	p.Thr955Thr	synonymous_variant	22/25		XP_047301826.1
TTC21B	XM_011511871.4	c.2769T>G	p.Thr923Thr	synonymous_variant	21/24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.3519T>G	p.Thr1173Thr	synonymous_variant	26/29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00266 AC: 667 AN: 251180 Hom.: 4 AF XY: 0.00264 AC XY: 358 AN XY: 135750

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00415

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00347 AC: 5077 AN: 1461808 Hom.: 17 Cov.: 32 AF XY: 0.00328 AC XY: 2384 AN XY: 727208

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.00259 AC: 395 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74444

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000822 Hom.: 19

Bravo AF: 0.00282

EpiCase AF: 0.00376

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TTC21B: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Asphyxiating thoracic dystrophy 4 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis 12 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jeune thoracic dystrophy;C0687120:Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.19
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs115504901; hg19: chr2-166740469;