rs386834024

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017739.4(POMGNT1):​c.1895+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,613,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 splice_donor, intron

Scores

2
3
2
Splicing: ADA: 0.9929
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 7.53
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 made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-46189457-C-A is Pathogenic according to our data. Variant chr1-46189457-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189457-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-46189457-C-A is described in Lovd as [Pathogenic]. Variant chr1-46189457-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POMGNT1NM_017739.4 linkc.1895+1G>T splice_donor_variant, intron_variant Intron 21 of 21 ENST00000371984.8 NP_060209.4 Q8WZA1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POMGNT1ENST00000371984.8 linkc.1895+1G>T splice_donor_variant, intron_variant Intron 21 of 21 1 NM_017739.4 ENSP00000361052.3 Q8WZA1-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152140
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:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000801
AC:
20
AN:
249666
Hom.:
0
AF XY:
0.0000592
AC XY:
8
AN XY:
135042
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000581
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000233
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
161
AN:
1461226
Hom.:
0
Cov.:
30
AF XY:
0.0000963
AC XY:
70
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000134
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000107
Hom.:
0
Bravo
AF:
0.0000793
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000107
AC:
13

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:2
Aug 21, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

Dec 03, 2018
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The homozygous c.1895+1G>T variant in POMGNT1 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.007982% (22/275604) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386834024). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.1895+1G>T variant may impact protein function with abnormal splicing and reduced translation (PMID: 22554691). However, these types of assays may not accurately represent biological function. This variant has been observed in the compound heterozygous state, with two variants not reported in ClinVar, in 2 individuals with LGMD as reported by the literature (PMID: 22554691, 22323514). The presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the c.1895+1G>T variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences reported in the literature in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PS3 (Richards 2015). -

POMGNT1-related disorder Pathogenic:2
May 03, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The POMGNT1 c.1895+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in at least four studies in which it is found in a compound heterozygous state in three individuals with muscle-eye-brain disease and in one individual with cobblestone lissencephaly (Diesen et al. 2004; Mercuri et al. 2009; Saredi et al. 2012; Devisme et al. 2012). The variant was absent from at least 125 control individuals and is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR experiments demonstrated that the variant affects splicing with retention of the intron between exons 21 and 22 (Saredi et al. 2012). Due to the potential impact of splice donor variants and the evidence from the literature, the c.1895+1G>T variant is classified as pathogenic for POMGNT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 14, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The POMGNT1 c.1895+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in several unrelated individuals with muscle-eye-brain disease (see for example, Saredi et al. 2012. PubMed ID: 22554691; Diesen et al. 2004. PubMed ID: 15466003). Functional RNA studies on this variant have shown it leads to retention of intron 21 (Saredi et al. 2012. PubMed ID: 22554691). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in POMGNT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:2
Mar 22, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 08, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Previously reported in individuals with POMGNT1-related disorders who harbor an additional POMGNT1 variant referred for genetic testing at GeneDx and in published literature (Diesen et al., 2004; Devisme et al., 2012; Saredi et al., 2012); Published functional studies demonstrate the splice defect leads to retention of intron 21 (Saredi et al., 2012); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29555514, 32115343, 22554691, 25525159, 17906881, 15466003, 19299310, 22323514, 28424332) -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:2
Mar 18, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 27, 2021
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_017739.3(POMGNT1):c.1895+1G>T is a canonical splice variant classified as pathogenic in the context of muscle-eye-brain disease. c.1895+1G>T has been observed in cases with relevant disease (PMID: 15466003, 19299310, 22323514, 28688748, 22554691). Functional assessments of this variant are available in the literature (PMID: 22554691). c.1895+1G>T has been observed in population frequency databases (gnomAD: FIN 0.02%). In summary, NM_017739.3(POMGNT1):c.1895+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Muscle eye brain disease Pathogenic:2
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Myopathy caused by variation in POMGNT1 Pathogenic:1
Oct 19, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with POMGNT-related disorders. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to result in intron 21 retention and a premature termination codon (PMID: 22554691; 28424332) (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative nucleotide change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other canonical splice variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar; PMID: 26908613). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with POMGNT1-related disorders (ClinVar; PMID: 22323514, 15466003, 28688748, 29555514, 28424332, 22554691) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1
Jul 02, 2018
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

The c.1895+1G>T variant in POMGNT1 has been previously reported in eight individuals with muscular dystrophy-dystroglycanopathy (PMID: 32115343, PMID: 29555514, PMID: 28688748, PMID: 22323514, PMID: 19299310, PMID: 15466003, PMID: 22554691, PMID: 28424332), and has been identified in 0.012% (15/128292) non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834024). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#:56593) and has been interpreted as pathogenic by Illumina (most recent interpretation; previously interpreted as VUS [2016] and likely pathogenic [2016]), Ambry Genetics, Centre for Mendelian Genomics,University Medical Centre Ljubljana, Broad Institute Rare Disease Group,GeneDx, Invitae, Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), Myriad Women's Health, Inc., Natera, Inc, PerkinElmer Genomics, and Counsyl. Of these eight affected individuals, one was a compound heterozygote who carried a pathogenic variant with unknown phase (PMID: 29555514) and one was a compound heterozygote who carried a likely pathogenic variant with unknown phase (PMID: 22323514), which increases the likelihood that the c.1895+1G>T variant is pathogenic. The variant was shown by RT-PCR analysis (PMID: 22554691) and muscle RNAseq of patient tissue (PMID: 28424332) to alter splicing and lead to intron retention between exons 21 and 22. This variant is located in the 5’ splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated 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_Moderate, PS3, PM3 (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 23, 2024
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
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 21 of the POMGNT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs386834024, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 15466003, 22554691, 28424332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56593). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in partial inclusion of intron 21 (also known as intron 25) and introduces a new termination codon (PMID: 28424332). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.94
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.25
Position offset: 27
DS_DL_spliceai
0.94
Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386834024; hg19: chr1-46655129; API