rs74374973

Positions:

chr1-46189973-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_017739.4(POMGNT1):c.1666G>A(p.Asp556Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,614,096 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0096 ( 6 hom., cov: 32)

Exomes 𝑓: 0.012 ( 114 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:14

Conservation

PhyloP100: 5.83

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010585457).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00956 (1457/152344) while in subpopulation AMR AF= 0.0145 (222/15306). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1666G>A	p.Asp556Asn	missense_variant	20/22	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.1666G>A	p.Asp556Asn	missense_variant	20/22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.00956

AC:

1456

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.00997

AC:

2503

AN:

251014

Hom.:

AF XY:

0.00972

AC XY:

1318

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00877

Gnomad ASJ exome

AF:

0.0323

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.0171

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0118

AC:

17243

AN:

1461752

Hom.:

114

Cov.:

AF XY:

0.0114

AC XY:

8314

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00946

Gnomad4 ASJ exome

AF:

0.0320

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.0155

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.00956

AC:

1457

AN:

152344

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

693

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00257

Gnomad4 AMR

AF:

0.0145

Gnomad4 ASJ

AF:

0.0328

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0157

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.00983

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0119

AC:

102

ExAC

AF:

0.00893

AC:

1084

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Pathogenic:1Uncertain:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Muscle eye brain disease

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	POMGNT1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 08, 2020	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Congenital Muscular Dystrophy, alpha-dystroglycan related

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa 76

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 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

Jan 31, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.0089

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.48

Sift

Benign

0.046

D;D

Sift4G

Benign

0.068

T;T

Polyphen

1.0

D;.

Vest4

0.64

MVP

0.92

MPC

0.42

ClinPred

0.0078

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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