rs267606960

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_017739.4(POMGNT1):c.1469G>A(p.Cys490Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000508 in 1,614,032 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C490G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.58

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 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_017739.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-46192169-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2067831.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 1-46192168-C-T is Pathogenic according to our data. Variant chr1-46192168-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46192168-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46192168-C-T is described in Lovd as [Pathogenic]. Variant chr1-46192168-C-T is described in Lovd as [Pathogenic]. Variant chr1-46192168-C-T 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.1469G>A	p.Cys490Tyr	missense_variant	Exon 17 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.1469G>A	p.Cys490Tyr	missense_variant	Exon 17 of 22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251488

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135922

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:

0.000163

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000891

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POMGNT1: PM3:Very Strong, PM1, PM2, PP3, PP4, PS3:Supporting -

May 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18195152, 17559086, 21361872, 19067344, 15466003, 17906881, 22323514, 24282183, 17878207, 17030669, 31589614) -

Mar 25, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscle eye brain disease

Pathogenic:2

Oct 17, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

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 p.Cys490Tyr variant in POMGNT1 has been reported in 8 individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 15466003, 22323514, 17559086, 24282183, 17030669), and has been identified in 0.006% (2/35440) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs267606960). 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 #4000) and has been interpreted as pathogenic by Invitae, Fulgent Genetics, CeGaT Center for Human Genetics Tuebingen, OMIM, and Natera, Inc, and as likely pathogenic by PerkinElmer Genomics and Counsyl. Of these 8 affected individuals, 3 were homozygotes, and at least 1 was a compound heterozygote that carried a pathogenic variant in trans, which increases the likelihood that the p.Cys490Tyr variant is pathogenic (PMID: 15466003, 22323514, 17559086, 24282183; ClinvarID: 265399). In vitro functional studies provide some evidence that the p.Cys490Tyr variant may impact protein function, as reflected by reduced catalytic activity in an in vitro enzymatic activity assay (PMID: 21361872). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: PM3_Strong, PM2_supporting, PS3_Supporting, PP3 (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

Jul 27, 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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 490 of the POMGNT1 protein (p.Cys490Tyr). This variant is present in population databases (rs267606960, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital muscular dystrophy, cobblestone lissencephaly, and muscle-eye-brain (MEB) disease (PMID: 15466003, 17030669, 17559086, 17878207, 22323514, 24282183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4000). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMGNT1 protein function. Experimental studies have shown that this missense change affects POMGNT1 function (PMID: 21361872). For these reasons, this variant has been classified as Pathogenic. -

POMGNT1-related disorder

Pathogenic:1

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POMGNT1 c.1469G>A variant is predicted to result in the amino acid substitution p.Cys490Tyr. This variant has been reported in homozygous and compound heterozygous states in individuals with POMGNT1-related disorders (Diesen et al. 2004. PubMed ID: 15466003; Raducu et al. 2013. PubMed ID: 24282183; Biancheri et al. 2006. PubMed ID: 17030669; Godfrey et al. 2007. PubMed ID: 17878207; Bouchet et al. 2007. PubMed ID: 17559086). A functional study showed the p.Cys490 substitution does not decrease protein expression, but does cause reduced catalytic activity (Voglmeir et al. 2011. PubMed ID: 21361872). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Jan 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

Feb 26, 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

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.5

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-9.1

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.95

Gain of phosphorylation at C490 (P = 0.0288);Gain of phosphorylation at C490 (P = 0.0288);

MVP

0.99

MPC

1.2

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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