rs746638187
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_017739.4(POMGNT1):c.550C>T(p.His184Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
POMGNT1
NM_017739.4 missense
NM_017739.4 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 9.55
Genes affected
POMGNT1 (HGNC:19139): (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-)) This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMGNT1 | NM_017739.4 | c.550C>T | p.His184Tyr | missense_variant | 7/22 | ENST00000371984.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMGNT1 | ENST00000371984.8 | c.550C>T | p.His184Tyr | missense_variant | 7/22 | 1 | NM_017739.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152270Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251228Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135890
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GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461752Hom.: 0 Cov.: 34 AF XY: 0.0000289 AC XY: 21AN XY: 727174
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74402
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 18, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 11, 2017 | - - |
Muscular dystrophy-dystroglycanopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.His184Tyr variant in POMGNT1 has been reported in one individual with muscular dystrophy-dystroglycanopathy (PMID: 30937090), and has also been identified in 0.009% (12/128998) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs746638187). 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. The variant has also been reported in ClinVar (Variation ID#: 471407) as a variant of uncertain significance by Invitae, Mayo Clinic Laboratories, Genetic Services Laboratory (University of Chicago), Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), and Natera, Inc. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.His184Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015). - |
Autosomal recessive limb-girdle muscular dystrophy type 2O Uncertain:1
Uncertain significance, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 184 of the POMGNT1 protein (p.His184Tyr). This variant is present in population databases (rs746638187, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of muscle-eye-brain disease (PMID: 30937090). ClinVar contains an entry for this variant (Variation ID: 471407). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Muscle eye brain disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
0.72
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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