1-165743172-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_019026.6(TMCO1):c.463C>T(p.Arg155*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,882 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 Likely pathogenic (★★).
Frequency
Consequence
NM_019026.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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TMCO1 | NM_019026.6 | c.463C>T | p.Arg155* | stop_gained | Exon 6 of 7 | ENST00000367881.11 | NP_061899.3 | |
TMCO1 | NM_001256164.1 | c.514C>T | p.Arg172* | stop_gained | Exon 6 of 7 | NP_001243093.1 | ||
TMCO1 | NM_001256165.1 | c.427C>T | p.Arg143* | stop_gained | Exon 6 of 7 | NP_001243094.1 | ||
TMCO1 | NR_045818.1 | n.557C>T | non_coding_transcript_exon_variant | Exon 6 of 7 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251388Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727194
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Pathogenic:3
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HP:0000028 (present);na:HP:0000104 (present);na:HP:0000122 (present);na:HP:0000175 (present);na:HP:0000407 (present);na:HP:0000486 (present);na:HP:0000717 (present);na:HP:0000750 (present);na:HP:0000766 (present);na:HP:0000902 (present);na:HP:0001141 (present);na:HP:0001263 (present);na:HP:0001642 (present);na:HP:0002650 (present);na:HP:0002744 (present);na:HP:0002937 (present);na:HP:0004482 (present);na:HP:0100336 (present);na:HP:0100337 (present) Pathogenic:1
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not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation, as the last 34 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 31102500, 32214227, 30755392, 36708876) -
Cerebro-facio-thoracic dysplasia Pathogenic:1
Variant summary: TMCO1 c.463C>T (p.Arg155X) results in a premature termination codon, predicted to cause a truncation of the encoded protein which may escape nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 251388 control chromosomes. c.463C>T has been reported in the literature in multiple individuals affected with Craniofacial Dysmorphism, Skeletal Anomalies, And Intellectual Disability Syndrome. These data indicate that the variant is very likely to be associated with disease (JI_2019, Sharkia_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30755392, 31102500). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at