1-46192097-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_Moderate PM2 PP3_Strong PP5

The NM_017739.4(POMGNT1):c.1539+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,613,632 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: POMGNT1 NM_017739.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23 U:1
• Conservation: PhyloP100: 7.48

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0630358 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-46192097-C-T is Pathogenic according to our data. Variant chr1-46192097-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56582.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=16, Uncertain_significance=1}. Variant chr1-46192097-C-T is described in Lovd as [Pathogenic]. Variant chr1-46192097-C-T is described in Lovd as [Pathogenic]. Variant chr1-46192097-C-T is described in Lovd as [Benign]. Variant chr1-46192097-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46192097-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMGNT1	NM_017739.4	c.1539+1G>A		splice_donor_variant		ENST00000371984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT1	ENST00000371984.8	c.1539+1G>A		splice_donor_variant		1	NM_017739.4	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000617 AC: 155 AN: 251296 Hom.: 0 AF XY: 0.000611 AC XY: 83 AN XY: 135826

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74470

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:23 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	The c.1539+1 G>A variant is reported as a common Finnish founder mutation (Diesen et al., 2004); Published functional studies demonstrate a damaging effect as c.1539+1 G>A causes read-through of intronic sequences, resulting in introduction of a premature termination codon (Yoshida et al., 2001); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 15466003, 11709191, 22323514, 23326386, 25525159, 26990548, 29555514, 30961548, 27604308, 31980526, 31589614, 33144682) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 09, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Muscle eye brain disease Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 27, 2020

Variant summary: POMGNT1 c.1539+1G>A 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and caused skipping of the upstream exon 17 (Predicted effect: p.Leu472_His513del, Yoshida_2001). The variant allele was found at a frequency of 0.00063 in 251850 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in POMGNT1 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00063 vs 0.0011), allowing no conclusion about variant significance. c.1539+1G>A has been reported in the literature in multiple individuals affected with Muscle-eye-brain disease including homozygotes (Yoshida_2001, ,Taniguchi_2003, Diesen_2004). These data indicate that the variant is very likely to be associated with disease. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and pathogenic (10x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 10, 2015

- -

Retinitis pigmentosa 76 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jun 14, 2015

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change affects a donor splice site in intron 17 of the POMGNT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs138642840, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with muscle-eye-brain disease and congenital muscular dystrophy (PMID: 11709191, 23326386). This variant is also known as IVS17+1G>A. ClinVar contains an entry for this variant (Variation ID: 56582). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 09, 2019

NM_017739.3(POMGNT1):c.1539+1G>A is classified as pathogenic in the context of POMGNT-related disorders. Sources cited for classification include the following: PMID 15466003 and 11709191. Classification of NM_017739.3(POMGNT1):c.1539+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Myopathy caused by variation in POMGNT1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

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) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-RNA analysis has shown this variant causes two aberrant splicing outcomes; a read-through of intronic sequences resulting in a premature stop codon, and exon-skipping leading to an in-frame deletion of 42 amino acids. (PMID: 11709191). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 178 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with POMGNT1-related disorders (ClinVar; VCGS). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Muscular dystrophy-dystroglycanopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The c.1539+1G>A variant in POMGNT1 has been reported in many individuals with muscular dystrophy-dystroglycanopathy (PMID: 17559086, 12588800, 22323514, 26013959, 1790688, 16427280, 11709191), and has been identified in 0.2% (49/25102) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs138642840). 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 #56582) and has been interpreted as pathogenic by multiple labs and of uncertain significance by Institute of Human Genetics (University of Leipzig Medical Center). Of the multiple affected individuals, at least 2 were homozygotes, and multiple were compound heterozygotes that carried reported pathogenic/likely pathogenic variants in trans, which increases the likelihood that the c.1539+1G>A variant is pathogenic (PMID: 17559086, 11709191, 6427280, 12588800, 26013959, 17906881). RT-PCR analysis performed on patient skeletal muscle showed altered splicing with transcripts having exon 17 skipping or intron retention leading to premature termination (PMID: 11709191). In vitro functional studies provide some evidence that the c.1539+1G>A variant may impact protein function (PMID: 11709191). However, these types of assays may not accurately represent biological function. 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. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1_Moderate, PS3, PM3_VeryStrong (Richards 2015). -

POMGNT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The POMGNT1 c.1539+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of available literature, the c.1539+1G>A variant has been identified in at least 35 individuals with POMGNT1-related disorders, including in a homozygous state in 25 individuals and in a compound heterozygous state in six individuals and five fetuses (Yoshida et al. 2001; Taniguchi et al. 2003; Deisen et al. 2004; Vajsar et al. 2006; Hehr et al. 2007; Bouchet et al. 2007; Godfrey et al. 2007; Teber et al. 2008; Devisme et al. 2012; Amir et al. 2016). The c.1539+1G>A variant was reported in three of 1000 control alleles in a heterozygous state and at a frequency of 0.00240 in the European (Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis confirmed that the variant disrupts splicing resulting in the skipping of exon 17 and premature truncation of the protein (Yoshida et al. 2001). Functional studies using targeted expression in HEK293 cells or fibroblasts from patients demonstrated that the POMGNT1 enzyme activity was significantly reduced (Yoshida et al. 2001; Vajsar et al. 2006). Based on the collective evidence, the c.1539+1G>A 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;C3150412:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O;C4310704:Retinitis pigmentosa 76 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs138642840; hg19: chr1-46657769;