Menu
GeneBe

rs386834034

Variant summary

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

The NM_017739.4(POMGNT1):c.643C>T(p.Arg215Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R215R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-46194853-G-A is Pathogenic according to our data. Variant chr1-46194853-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 56604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46194853-G-A is described in Lovd as [Pathogenic]. Variant chr1-46194853-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POMGNT1NM_017739.4 linkuse as main transcriptc.643C>T p.Arg215Ter stop_gained 7/22 ENST00000371984.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POMGNT1ENST00000371984.8 linkuse as main transcriptc.643C>T p.Arg215Ter stop_gained 7/221 NM_017739.4 P1Q8WZA1-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151972
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251028
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461826
Hom.:
0
Cov.:
34
AF XY:
0.00000963
AC XY:
7
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151972
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74230
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000330
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Muscle eye brain disease Pathogenic:3
Likely pathogenic, no assertion criteria providedclinical testingCounsylJan 02, 2014- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Oct 01, 2020- -
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Muscular dystrophy-dystroglycanopathy Pathogenic:2
Pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 24, 2023The p.Arg215Ter variant in POMGNT1 has been reported in at least two individuals with muscular dystrophy-dystroglycanopathy (PMID: 22554691, 26938784), and has been identified in 0.006% (2/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834034). 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#: 56604) and has been interpreted as pathogenic/likely pathogenic by multiple labs. Of the two affected individuals reported, one was a compound heterozygote who carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg215Ter variant is pathogenic (PMID: 22554691, ClinVarID: 56610). cDNA sequencing analysis performed on affected tissue shows exon 7 skipping, which is out-of-frame exon (PMID:22554691). This nonsense variant leads to a premature termination codon at position 215, which is predicted to lead to a truncated or absent protein. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3, PS3 (Richards 2015). -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, 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 POMGNT1-related disorders. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic and likely pathogenic in ClinVar in individuals with POMGNT1-related disorders. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 14, 2017The R215X variant in the POMGNT1 gene has been reported previously in the homozygous state in an individual with severe intellectual disability, hypotonia, pachygyria, polymicrogyria, and seizures (Stark et al., 2016). It has also been reported in the compound heterozygous state, along with a second nonsense variant, in an individual with muscle eye brain disease (Saredi et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R215X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R215X as a pathogenic variant. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2022POMGNT1: PVS1, PM3:Strong, PM2 -
Retinitis pigmentosa 76 Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCounsylJan 02, 2014- -
Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCounsylJan 02, 2014- -
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 06, 2023This sequence change creates a premature translational stop signal (p.Arg215*) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs386834034, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 22554691, 26938784, 28832562). 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: 56604). 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
Likely pathogenic, no assertion criteria providedclinical testingCounsylJan 02, 2014- -
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 24, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
39
Dann
Uncertain
1.0
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.88
D
MutationTaster
Benign
1.0
A;A;A;A;D
Vest4
0.85
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.26
Position offset: -9

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: rs386834034; hg19: chr1-46660525; COSMIC: COSV100915579; COSMIC: COSV100915579; API