rs386834022

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_017739.4(POMGNT1):​c.1876delG​(p.Val626SerfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000124 in 1,613,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V626V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.60

Publications

1 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PP5
Variant 1-46189476-AC-A is Pathogenic according to our data. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189476-AC-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMGNT1NM_017739.4 linkc.1876delG p.Val626SerfsTer8 frameshift_variant Exon 21 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.1876delG p.Val626SerfsTer8 frameshift_variant Exon 21 of 22 1 NM_017739.4 ENSP00000361052.3 Q8WZA1-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000400
AC:
1
AN:
249874
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461302
Hom.:
0
Cov.:
30
AF XY:
0.00000963
AC XY:
7
AN XY:
726884
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44624
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86100
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1111758
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74286
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41400
American (AMR)
AF:
0.00
AC:
0
AN:
15262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:2
Feb 10, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Muscle eye brain disease Pathogenic:2
Oct 20, 2014
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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. -

-
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 Pathogenic:1
Apr 29, 2025
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

The p.Val626SerfsTer8 variant in POMGNT1 has been reported in one individual with muscular dystrophy-dystroglycanopathy (PMID: 11709191), and has been identified in 0.001% (17/1179772) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834022). 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. It is of note that this variant occurs in a homopolymer repeat, which could indicate that it exists as an artifact from sequencing. However, disease-causing variants have been reported in homopolymer regions, so this is not enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VCV000056591.9) and has been interpreted as likely pathogenic/pathogenic by multiple submitters. In vitro functional studies provide some evidence that the p.Val626SerfsTer8 variant may impact protein function (PMID: 12788071). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 626 and leads to a premature termination codon 8 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. There are a number of pathogenic variants downstream of this variant in ClinVar, suggesting that this variant is in a functional domain and supports pathogenicity. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive muscular dystrophy-dystroglycanopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1_strong, PS3_supporting, PM2_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
May 31, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1
Dec 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Val626Serfs*8) in the POMGNT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the POMGNT1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with muscle-eye-brain disease (PMID: 12849864). This variant is also known as 1970delG (frameshift at Val626 and a premature termination codon at codon 633). ClinVar contains an entry for this variant (Variation ID: 56591). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects POMGNT1 function (PMID: 12788071). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.6
Mutation Taster
=2/198
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs386834022; hg19: chr1-46655148; API