rs34489989

chr2-165901892-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_024753.5(TTC21B):c.2587C>T(p.Arg863Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,102 control chromosomes in the GnomAD database, including 3 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. R863Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2 O:1
• Conservation: PhyloP100: 2.66

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23543653).
• BP6: Variant 2-165901892-G-A is Benign according to our data. Variant chr2-165901892-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195531.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC21B	NM_024753.5	c.2587C>T	p.Arg863Trp	missense_variant	20/29	ENST00000243344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC21B	ENST00000243344.8	c.2587C>T	p.Arg863Trp	missense_variant	20/29	1	NM_024753.5	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151302 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000816 AC: 205 AN: 251304 Hom.: 0 AF XY: 0.000832 AC XY: 113 AN XY: 135840

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00188 AC: 2744 AN: 1461686 Hom.: 3 Cov.: 32 AF XY: 0.00183 AC XY: 1328 AN XY: 727152

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00103 AC: 156 AN: 151416 Hom.: 0 Cov.: 32 AF XY: 0.000812 AC XY: 60 AN XY: 73890

Gnomad4 AFR AF: 0.000364

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000290

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000982

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00164

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously in the heterozygous state in an individual with Bardet-Biedl syndrome; however, no second variant was identified (Redin et al., 2012); This variant is associated with the following publications: (PMID: 22773737) -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 10, 2019	The TTC21B c.2587C>T; p.Arg863Trp variant (rs34489989) has been described in an individual who reportedly fulfilled diagnostic inclusion criteria for Bardet-Biedl syndrome (Redin 2012). It is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 195531), and is observed in the general population at an overall frequency of 0.084% (237/282480 alleles), with increased frequency in the non-Finnish European population (0.17%) in the Genome Aggregation Database. The arginine at codon 863 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious to protein structure/function. However, due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Redin C et al. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet 2012;9(8):502-512. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTC21B: PM2 -

Asphyxiating thoracic dystrophy 4 Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephronophthisis 12 (MIM#613820), short-rib thoracic dysplasia 4 with or without polydactyly (MIM#613819) and familial focal segmental glomerulosclerosis (FSGS). Partial loss of function has also been described, and associated with hypomorphic variants in this gene (OMIM, PMIDs: 24876116, 21258341). (I) 0106 - This gene is associated with autosomal recessive disease. Although OMIM refers to the association of this gene with autosomal dominant nephronophthisis 12 (MIM#613820), no specific evidence was found in the literature confirming this observation. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 237 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.R863Q: 11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TPR-repeat motif (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a variant of uncertain significance by clinical diagnostic laboratories and is heterozygous in one individual with autosomal recessive Bardet-Biedl syndrome, with no classification provided (ClinVar, PMID: 22773737). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

TTC21B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.49
MPC		0.24
ClinPred		0.19	T
GERP RS		3.8
Varity_R		0.53
gMVP		0.50

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: rs34489989; hg19: chr2-166758402; COSMIC: COSV99693093;