rs2292487

Positions:

chr1-46194623-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017739.4(POMGNT1):c.681A>G(p.Lys227Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,968 control chromosomes in the GnomAD database, including 103,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K227?) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.35 ( 9438 hom., cov: 33)

Exomes 𝑓: 0.35 ( 93734 hom. )

Consequence

POMGNT1
NM_017739.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.397

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029520392).

BP6

Variant 1-46194623-T-C is Benign according to our data. Variant chr1-46194623-T-C is described in ClinVar as [Benign]. Clinvar id is 95761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46194623-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.397 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.681A>G	p.Lys227Lys	synonymous_variant	8/22	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.681A>G	p.Lys227Lys	synonymous_variant	8/22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53060

AN:

151964

Hom.:

9428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.350

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.353

Gnomad OTH

AF:

0.350

GnomAD3 exomes

AF:

0.355

AC:

89316

AN:

251468

Hom.:

16649

AF XY:

0.358

AC XY:

48697

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.389

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.446

Gnomad FIN exome

AF:

0.392

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.354

AC:

518207

AN:

1461886

Hom.:

93734

Cov.:

AF XY:

0.358

AC XY:

260087

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.361

Gnomad4 AMR exome

AF:

0.388

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.450

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.352

Gnomad4 OTH exome

AF:

0.342

GnomAD4 genome

AF:

0.349

AC:

53131

AN:

152082

Hom.:

9438

Cov.:

AF XY:

0.351

AC XY:

26109

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.350

Gnomad4 AMR

AF:

0.362

Gnomad4 ASJ

AF:

0.313

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.435

Gnomad4 FIN

AF:

0.384

Gnomad4 NFE

AF:

0.353

Gnomad4 OTH

AF:

0.353

Alfa

AF:

0.356

Hom.:

8045

Bravo

AF:

0.343

TwinsUK

AF:

0.340

AC:

1260

ALSPAC

AF:

0.348

AC:

1342

ESP6500AA

AF:

0.351

AC:

1548

ESP6500EA

AF:

0.349

AC:

3000

ExAC

AF:

0.355

AC:

43071

Asia WGS

AF:

0.288

AC:

1002

AN:

3478

EpiCase

AF:

0.337

EpiControl

AF:

0.333

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Lys227Lys in exon 8 of POMGNT1: This variant is not expected to have clinical significance because it has been identified in 35% (3000/8600) of European Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs2292487). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Retinitis pigmentosa 76

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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

Feb 01, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Muscle eye brain disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.2

DANN

Benign

0.97

DEOGEN2

Benign

0.0022

Eigen

Benign

-0.047

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.14

REVEL

Benign

0.048

Sift

Uncertain

0.018

Sift4G

Benign

0.19

Vest4

0.031

ClinPred

0.011

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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