8-93754922-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_153704.6(TMEM67):c.8C>T(p.Thr3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T3T) has been classified as Likely benign.
Frequency
Consequence
NM_153704.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251084Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135766
GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461484Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727038
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.8C>T (p.T3M) alteration is located in exon 1 (coding exon 1) of the TMEM67 gene. This alteration results from a C to T substitution at nucleotide position 8, causing the threonine (T) at amino acid position 3 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 Uncertain:1
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Meckel-Gruber syndrome;C0431399:Joubert syndrome Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3 of the TMEM67 protein (p.Thr3Met). This variant is present in population databases (rs779950527, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. 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 TMEM67 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at