1-46189457-C-A

Variant names:

• chr1-46189457-C-A
• rs386834024
• NM_017739.4:c.1895+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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: Splicing: ADA: 0.9929
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.53
• Publications: 4 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• PP5: Variant 1-46189457-C-A is Pathogenic according to our data. Variant chr1-46189457-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56593.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
POMGNT1	NM_017739.4	c.1895+1G>T		splice_donor_variant, intron_variant	Intron 21 of 21	ENST00000371984.8	NP_060209.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8	c.1895+1G>T		splice_donor_variant, intron_variant	Intron 21 of 21	1	NM_017739.4	ENSP00000361052.3

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000801 AC: 20 AN: 249666 AF XY: 0.0000592

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000672 AC: 3 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111702

Other (OTH) AF: 0.000133 AC: 8 AN: 60362

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000968 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:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:3

May 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POMGNT1 c.1895+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of POMGNT1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Cummings_2017). The variant allele was found at a frequency of 8e-05 in 249666 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POMGNT1 causing Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, allowing no conclusion about variant significance. c.1895+1G>T has been observed in individual(s) affected with Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 (example: Cummings_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28424332). ClinVar contains an entry for this variant (Variation ID: 56593). Based on the evidence outlined above, the variant was classified as pathogenic. -

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. -

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). -

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) -

POMGNT1-related disorder Pathogenic:2

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. -

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. -

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
PhyloP100		7.5
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs386834024; hg19: chr1-46655129;