1-46192181-G-C

Position:

chr1-46192181-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_017739.4(POMGNT1):c.1456C>G(p.Arg486Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.52

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:

POMGNT1 (HGNC:):

POMGNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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, 6 uncertain in NM_017739.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.1456C>G	p.Arg486Gly	missense_variant	17/22	ENST00000371984.8	NP_060209.4	Q8WZA1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8 linkuse as main transcript	c.1456C>G	p.Arg486Gly	missense_variant	17/22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251494

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 30, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2022

The c.1456C>G (p.R486G) alteration is located in exon 17 (coding exon 16) of the POMGNT1 gene. This alteration results from a C to G substitution at nucleotide position 1456, causing the arginine (R) at amino acid position 486 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 486 of the POMGNT1 protein (p.Arg486Gly). This variant is present in population databases (rs534543454, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POMGNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 291060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POMGNT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Muscle eye brain disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

2.0

M;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.60

P;.

Vest4

0.53

MutPred

0.58

Loss of stability (P = 0.046);Loss of stability (P = 0.046);

MVP

0.81

MPC

0.33

ClinPred

0.94

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.64

gMVP

0.71

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