1-46189870-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017739.4(POMGNT1):c.1769G>A(p.Trp590*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,762 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017739.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249968Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134958
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461600Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727070
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Muscle eye brain disease Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 17, 2021 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 28, 2015 | - - |
Muscular dystrophy-dystroglycanopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Trp590Ter variant in POMGNT1 has been reported in one individual with muscular dystrophy-dystroglycanopathy (PMID: 15466003), and has been identified in 0.002% (2/128260) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834019). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#:56587) and has been interpreted as pathogenic by Invitae, Genomics England, and Natera, Inc, probable-pathogenic by the Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) and likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg590Ter variant may impact protein function, as reflected by reduced catalytic activity in an in vitro enzymatic activity assay (PMID: 21361872). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 590, which is predicted to lead to a truncated or absent protein. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS3_Supporting (Richards 2015). - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O;C3151519:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3;C4310704:Retinitis pigmentosa 76 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
Retinitis pigmentosa 76 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Trp590*) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs386834019, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with muscle-eye-brain (MEB) disease (PMID: 15466003, 21361872). ClinVar contains an entry for this variant (Variation ID: 56587). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at