chr8-93795448-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_153704.6(TMEM67):c.1714G>A(p.Ala572Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_153704.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152002Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 572 of the TMEM67 protein (p.Ala572Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 25326635). 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: 521968). 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 expected to disrupt TMEM67 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not specified Uncertain:1
This sequence change, c.1714G>A, in exon 17 results in an amino acid change, p.Ala572Thr. This sequence change is absent from the gnomAD population database. This sequence change does not appear to have been previously described in patients with TMEM67-related disorders. However, a different sequence change affecting the same amino acid (p.Ala572Val) has been reported in the compound heterozygous state in one autopsied fetus with bilateral enlarged cystic kidneys, ductal plate malformation in the liver and abnormal lung lobulation (PMID: 29194579). This p.Ala572Thr change affects a moderately conserved amino acid residue located in the transmembrane domain of the TMEM67 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala572Thr substitution. Due to the lack of functional studies, the clinical significance of the p.Ala572Thr change remains unknown at this time. -
Inborn genetic diseases Uncertain:1
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Joubert syndrome 6 Uncertain:1
This variant was found once in our laboratory in trans with another variant (F590S) in a 7-year-old female with a clinical diagnosis of Joubert syndrome. -
TMEM67-related disorder Uncertain:1
The TMEM67 c.1714G>A variant is predicted to result in the amino acid substitution p.Ala572Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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