1-46196784-C-T

Position:

chr1-46196784-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_017739.4(POMGNT1):c.301G>A(p.Val101Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,190 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 28 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 4.44

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:

POMGNT1 (HGNC:):

POMGNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_017739.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0067639947).

BP6

Variant 1-46196784-C-T is Benign according to our data. Variant chr1-46196784-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95759.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=4}. Variant chr1-46196784-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00245 (373/152348) while in subpopulation AMR AF= 0.00327 (50/15310). AF 95% confidence interval is 0.00254. There are 6 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.301G>A	p.Val101Ile	missense_variant	4/22	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.301G>A	p.Val101Ile	missense_variant	4/22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.00245

AC:

373

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0470

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00314

AC:

789

AN:

251406

Hom.:

AF XY:

0.00300

AC XY:

408

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0459

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00212

AC:

3098

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1526

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.0450

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00245

AC:

373

AN:

152348

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.0470

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00182

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00295

AC:

358

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	POMGNT1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 08, 2019	- -

Muscle eye brain disease

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

POMGNT1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0025

T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.51

.;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.41

N;N;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.033

B;B;.

Vest4

0.24

MVP

0.45

MPC

0.20

ClinPred

0.015

GERP RS

5.1

Varity_R

0.15

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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