rs386834018
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017739.4(POMGNT1):c.1738C>T(p.Arg580Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,900 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R580R) has been classified as Uncertain significance. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMGNT1 | NM_017739.4 | c.1738C>T | p.Arg580Ter | stop_gained | 20/22 | ENST00000371984.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMGNT1 | ENST00000371984.8 | c.1738C>T | p.Arg580Ter | stop_gained | 20/22 | 1 | NM_017739.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250670Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135438
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461736Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727158
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Muscle eye brain disease Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 15, 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 | Mar 12, 2014 | - - |
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.Arg580Ter variant in POMGNT1 has been reported in two individuals with muscular dystrophy-dystroglycanopathy (PMID: 17906881, 19067344), and has been identified in 0.0009% (1/113260) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834018). 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#:56586) and has been interpreted as pathogenic by Invitae, Natera, Inc, and Juha Muilu Group (Institute for Molecular Medicine Finland (FIMM)) and likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg580Ter 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 580, 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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56586). This premature translational stop signal has been observed in individuals with muscular dystrophy-dystroglycanopathy (PMID: 17906881, 19067344). This variant is present in population databases (rs386834018, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg580*) 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). - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at