1-46189539-C-T

Position:

chr1-46189539-C-T

Variant summary

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

The NM_017739.4(POMGNT1):c.1814G>A(p.Arg605His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,460,602 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. R605C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

POMGNT1
NM_017739.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.53

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-46189539-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 1-46189539-C-T is Pathogenic according to our data. Variant chr1-46189539-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46189539-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46189539-C-T is described in Lovd as [Pathogenic]. Variant chr1-46189539-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.1814G>A	p.Arg605His	missense_variant	21/22	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.1814G>A	p.Arg605His	missense_variant	21/22	1	NM_017739.4	ENSP00000361052.3		Q8WZA1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248792

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134430

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:

0.0000936

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460602

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726450

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	Published functional studies demonstrate a complete loss of catalytic activity (PMID: 21361872); 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: 17906881, 20215985, 17154333, 12849864, 33726816, 33200426, 31964843, 35846108, 24731844, 21361872) -

Muscle eye brain disease

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 10, 2014	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The p.Arg605His variant in POMGNT1 has been reported in at least six individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 33726816, 17154333, 12849864, 17906881, 20215985), and has been identified in 0.009% (2/21378) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267606962). 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 #56589) as pathogenic by Invitae and GeneDx, as probable-pathogenic by Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), and as Likely Pathogenic by Counsyl and the Clinical Genetics Karolinska University Hospital (Karolinska University Hospital). Of the six affected individuals, two were homozygous, and two were compound heterozygotes who carried pathogenic/likely pathogenic variants in trans, which increases the likelihood that the p.Arg605His variant is pathogenic (PMID: 33726816, 17154333, 12849864, 17906881). In vitro functional studies provide some evidence that the p.Arg605His 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 31, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

This variant is also known as G1908A. This missense change has been observed in individuals with muscle-eye-brain disease (PMID: 12849864, 21361872). This variant is present in population databases (rs267606962, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 605 of the POMGNT1 protein (p.Arg605His). ClinVar contains an entry for this variant (Variation ID: 56589). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg605 amino acid residue in POMGNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19679478, 21361872, 24731844; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects POMGNT1 function (PMID: 21361872). 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 expected to disrupt POMGNT1 protein function. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.96

Loss of MoRF binding (P = 0.0084);Loss of MoRF binding (P = 0.0084);

MVP

0.95

MPC

1.0

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.88

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