rs786204789
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_019026.6(TMCO1):c.87_90del(p.Val30ThrfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
TMCO1
NM_019026.6 frameshift
NM_019026.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.96
Genes affected
TMCO1 (HGNC:18188): (transmembrane and coiled-coil domains 1) This locus encodes a transmembrane protein. Mutations at this locus have been associated with craniofacial dysmorphism, skeletal anomalies, and cognitive disability. Mutations at this locus have also been associated with open angle glaucoma blindness. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-165768249-AAACC-A is Pathogenic according to our data. Variant chr1-165768249-AAACC-A is described in ClinVar as [Pathogenic]. Clinvar id is 189248.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMCO1 | NM_019026.6 | c.87_90del | p.Val30ThrfsTer9 | frameshift_variant | 2/7 | ENST00000367881.11 | |
TMCO1 | NM_001256165.1 | c.51_54del | p.Val18ThrfsTer9 | frameshift_variant | 2/7 | ||
TMCO1 | NM_001256164.1 | c.147-9_147-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
TMCO1 | NR_045818.1 | n.181_184del | non_coding_transcript_exon_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMCO1 | ENST00000367881.11 | c.87_90del | p.Val30ThrfsTer9 | frameshift_variant | 2/7 | 1 | NM_019026.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2014 | The Val81ThrfsX9 variant in TMCO1 has not been previously reported in individuals with disease or in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 81 and lead to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete TCMO1 loss-of-function is an established disease mechanism in autosomal recessive cerebrofaciothoracic dysplasia (Xin 2010, Caglayan 2013, Alanay 2014, Pehlivan 2014). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at