1-46192528-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

Genomes: not found (cov: 32)

Consequence

POMGNT1
NM_017739.4 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 7.32

Publications

3 publications found
Variant links:
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]
TSPAN1 (HGNC:20657): (tetraspanin 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_017739.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMGNT1NM_017739.4 linkc.1274G>C p.Trp425Ser missense_variant Exon 15 of 22 ENST00000371984.8 NP_060209.4 Q8WZA1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POMGNT1ENST00000371984.8 linkc.1274G>C p.Trp425Ser missense_variant Exon 15 of 22 1 NM_017739.4 ENSP00000361052.3 Q8WZA1-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251332
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1
Aug 31, 2016
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

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
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Muscular dystrophy-dystroglycanopathy Uncertain:1
Jan 24, 2023
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.5
M;M
PhyloP100
7.3
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-13
D;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.97
Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);
MVP
0.99
MPC
1.1
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.96
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
2.0
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs386834011; hg19: chr1-46658200; API