rs190057175

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_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

Publications

10 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 1-46194860-G-A is Pathogenic according to our data. Variant chr1-46194860-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 265399.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 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

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251122

AF XY:

0.0000294

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1112006

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41520

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000619

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

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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) -

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

Pathogenic:2

Mar 05, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

Muscle eye brain disease

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.0

Mutation Taster

=86/14

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over