chr1-46192528-C-G
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_017739.4(POMGNT1):c.1274G>C(p.Trp425Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_017739.4 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251332 AF XY: 0.00000736 show subpopulations
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Muscle eye brain disease Pathogenic:1
- -
Muscular dystrophy-dystroglycanopathy Uncertain:1
The p.Trp425Ser variant in POMGNT1 has been previously reported in the literature in two individuals with muscular dystrophy-dystroglycanopathy (PMID: 23453855, 15466003), and has been identified in 0.005438% (1/18390) East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834011). 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#:56577) as likely pathogenic for muscular dystrophy-dystroglycanopathy by Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) and Counsyl. Of these two affected individuals, one was a homozygote, which increases the likelihood that the p.Trp425Ser variant is pathogenic (PMID: 23453855). In vitro functional studies provide some evidence that the p.Trp425Ser 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. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Trp425Ser variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3 (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at