2-165941034-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_024753.5(TTC21B):āc.703G>Cā(p.Ala235Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_024753.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTC21B | NM_024753.5 | c.703G>C | p.Ala235Pro | missense_variant | Exon 6 of 29 | ENST00000243344.8 | NP_079029.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152176Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461494Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727040
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74352
ClinVar
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:2
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Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Uncertain:1
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Jeune thoracic dystrophy;C0687120:Nephronophthisis Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 235 of the TTC21B protein (p.Ala235Pro). This variant is present in population databases (rs150742619, gnomAD 0.02%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446647). 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. -
TTC21B-related disorder Uncertain:1
The TTC21B c.703G>C variant is predicted to result in the amino acid substitution p.Ala235Pro. This variant was reported in addition to two other variants in this gene in an individual with short rib polydactyly syndrome (Table S2, Zhang et al 2018. PubMed ID: 29068549). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD. 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