21-44499887-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_144991.3(TSPEAR):c.1906G>A(p.Gly636Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,607,132 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_144991.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSPEAR | ENST00000323084.9 | c.1906G>A | p.Gly636Ser | missense_variant | Exon 12 of 12 | 1 | NM_144991.3 | ENSP00000321987.4 | ||
TSPEAR | ENST00000642437.1 | n.*1851G>A | non_coding_transcript_exon_variant | Exon 13 of 13 | ENSP00000496535.1 | |||||
TSPEAR | ENST00000642437.1 | n.*1851G>A | 3_prime_UTR_variant | Exon 13 of 13 | ENSP00000496535.1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000688 AC: 16AN: 232470Hom.: 0 AF XY: 0.0000548 AC XY: 7AN XY: 127736
GnomAD4 exome AF: 0.000126 AC: 183AN: 1454914Hom.: 1 Cov.: 31 AF XY: 0.000109 AC XY: 79AN XY: 723550
GnomAD4 genome AF: 0.000105 AC: 16AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74362
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1906G>A (p.G636S) alteration is located in exon 12 (coding exon 12) of the TSPEAR gene. This alteration results from a G to A substitution at nucleotide position 1906, causing the glycine (G) at amino acid position 636 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 636 of the TSPEAR protein (p.Gly636Ser). This variant is present in population databases (rs782367814, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of ectodermal dysplasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2074348). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TSPEAR protein function with a negative predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at