2-165874774-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_024753.5(TTC21B):c.3932G>A(p.Arg1311His) variant causes a missense change. The variant allele was found at a frequency of 0.000914 in 1,613,496 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1311G) has been classified as Likely benign.
Frequency
Consequence
NM_024753.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTC21B | NM_024753.5 | c.3932G>A | p.Arg1311His | missense_variant | Exon 29 of 29 | ENST00000243344.8 | NP_079029.3 | |
TTC21B | XM_047445870.1 | c.3278G>A | p.Arg1093His | missense_variant | Exon 25 of 25 | XP_047301826.1 | ||
TTC21B | XM_011511871.4 | c.3182G>A | p.Arg1061His | missense_variant | Exon 24 of 24 | XP_011510173.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000552 AC: 84AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000554 AC: 139AN: 251086Hom.: 0 AF XY: 0.000538 AC XY: 73AN XY: 135678
GnomAD4 exome AF: 0.000951 AC: 1390AN: 1461322Hom.: 2 Cov.: 30 AF XY: 0.000937 AC XY: 681AN XY: 726996
GnomAD4 genome AF: 0.000552 AC: 84AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:6
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Reported in heterozygous state in a patient with renal and genital anomalies (Hilger et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26294094, 21258341) -
The TTC21B c.3932G>A; p.Arg1311His variant (rs139327086) is reported in the literature in an individual with renal and genital anomalies (Hilger 2015). This variant is also reported in ClinVar (Variation ID: 219735). It is observed in the general population with an overall allele frequency of 0.05% (151/282482 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.25). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hilger AC et al. Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association. Hum Mutat. 2015 Dec;36(12):1150-4. PMID: 26294094. -
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BP4 -
TTC21B: PM2, BP4 -
Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Uncertain:1
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Asphyxiating thoracic dystrophy 4 Uncertain:1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Jeune thoracic dystrophy;C0687120:Nephronophthisis Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1311 of the TTC21B protein (p.Arg1311His). This variant is present in population databases (rs139327086, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinically-diverse ciliopathies (PMID: 21258341). ClinVar contains an entry for this variant (Variation ID: 219735). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTC21B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Nephronophthisis 12 Uncertain:1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
TTC21B-related disorder Uncertain:1
The TTC21B c.3932G>A variant is predicted to result in the amino acid substitution p.Arg1311His. This variant was reported in the heterozygous state in an individual with renal and genital anomalies (Hilger et al. 2015. PubMed ID: 26294094). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at