chr1-46194860-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_017739.4(POMGNT1):c.636C>T(p.Phe212Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.04

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]

POMGNT1 links:

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]

TSPAN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-46194860-G-A is Pathogenic according to our data. Variant chr1-46194860-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46194860-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-46194860-G-A is described in Lovd as [Pathogenic]. Variant chr1-46194860-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMGNT1	NM_017739.4 link	c.636C>T	p.Phe212Phe	synonymous_variant	Exon 7 of 22	ENST00000371984.8	NP_060209.4	Q8WZA1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8 link	c.636C>T	p.Phe212Phe	synonymous_variant	Exon 7 of 22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251122

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000780

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 03, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in the homozygous and compound heterozygous state in patients with POMGNT1-related disorders (PMID: 17559086, 18330676, 23326386, 28424332, 32627857); This variant is demonstrated to destroy the canonical splice donor site and result in loss of function (PMID: 18330676); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18330676, 22323514, 23326386, 19299310, 28424332, 28492532, 31589614, 35175440, 37342771, 38444904, 37597066, 17559086, 32627857) -

Dec 02, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscle eye brain disease

Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Feb 02, 2023

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.636C>T alters a conserved nucleotide resulting in a synonymous change. 1/4 computational tools predicted weakening of the canonical 5' splice donor site. Multiple reports have demonstrated that this silent variant leads to exon 7 skipping, when analyzed at the RNA level (examples: Cummings_2017 and Oliveira_2008). The variant allele was found at a frequency of 4e-05 in 251122 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in POMGNT1 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4e-05 vs 0.00072), allowing no conclusion about variant significance. c.636C>T has been reported in the literature in individuals affected with muscular dystrophy and lissencephaly (examples: Bouchet_2007, Cummings_2017 and Oliveira_2008). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Jan 24, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.636C>T (p.Phe212=) variant in POMGNT1 has been reported in six individuals with muscular dystrophy-dystroglycanopathy (PMID 23326386, PMID 28424332, PMID 22323514, PMID 17559086, PMID 18330676) and has been identified in 0.01004% (2/19924) East Asian chromosomes in gnomAD (dbSNP ID rs190057175). 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 been reported in ClinVar (Variation ID #265399) as pathogenic by GeneDx, Invitae, Counsyl, CeGaT Center for Human Genetics Tuebingen, Natera, Inc, and Perkin-Elmer Genomics. Of these six affected individuals, one was a homozygote (PMID: 18330676) and two were compound heterozygotes, one confirmed compound heterozygote who carried a pathogenic variant in confirmed trans (PMID: 28424332) and one compound heterozygote who carried a likely pathogenic variant in trans (PMID: 22323514), which increases the likelihood that the c.636C>T (p.Phe212=) variant is pathogenic. The variant was shown by RT-PCR analysis (PMID: 18330676, PMID: 17559086) and muscle RNAseq of patient tissue (PMID: 28424332) to alter splicing and lead to exon skipping of exon 7, frameshift, and premature truncation. 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: PM3_Strong, PM2_supporting, PS3_Strong (Richards 2015). -

Retinitis pigmentosa 76

Pathogenic:1

Jan 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Pathogenic:1

Jan 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 09, 2021

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

Oct 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 212 of the POMGNT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POMGNT1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs190057175, gnomAD 0.006%). This variant has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 17559086, 18330676, 22323514, 23326386, 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: 265399). Studies have shown that this variant results in skipping of exon 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17559086, 18330676). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Jan 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.42

Position offset: -16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over