rs760705290

chr1-46192124-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_017739.4(POMGNT1):c.1513G>A(p.Gly505Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,834 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G505A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: POMGNT1 NM_017739.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 7.48

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]

TSPAN1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_017739.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-46192124-C-T is Pathogenic according to our data. Variant chr1-46192124-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553478.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=3}. Variant chr1-46192124-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46192124-C-T is described in Lovd as [Pathogenic]. Variant chr1-46192124-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-46192124-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMGNT1	NM_017739.4	c.1513G>A	p.Gly505Ser	missense_variant	17/22	ENST00000371984.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT1	ENST00000371984.8	c.1513G>A	p.Gly505Ser	missense_variant	17/22	1	NM_017739.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251444 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscle eye brain disease Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 28, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 03, 2021

Variant summary: POMGNT1 c.1513G>A (p.Gly505Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251444 control chromosomes. c.1513G>A has been reported in the literature as compound heterozygous/homozygous genotype among comprehensively genotyped individuals affected with CMD-MR, congenital muscular dystrophy with mental retardation (Song_2021), Muscle-eye-brain (MEB) disease, which is a congenital muscular dystrophy (CMD) phenotype (Jiao_2013), family with autosomal recessive Intellectual disability where authors note that POMGNT1 has solid evidence linking it to congenital dystroglycanopathy with MR (Hu_2019) and has been subsequently by others. These data indicate that the variant is very likely to be associated with disease. At-least one of these studies reported missense variants in POMGNT1 as accounting for over 66% of the mutational spectrum and as the most frequent pathogenic gene (24%) in the CMD group of patients (Song_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing one but not all publications utilized in the context of this evaluation. Based on the evidence outlined above (ACMG PS4/PP1, PM2, PM3, PP2, PP3) the variant was classified as pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POMGNT1 related disorder (PMID:23689641, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23689641, PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.879, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 505 of the POMGNT1 protein (p.Gly505Ser). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMGNT1 protein function. ClinVar contains an entry for this variant (Variation ID: 553478). This missense change has been observed in individual(s) with clinical features of POMGNT1-related conditions (PMID: 23689641, 29302074, 32404165). This variant is present in population databases (rs760705290, gnomAD 0.007%). -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 26, 2023

- -

Muscular dystrophy-dystroglycanopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 24, 2023

The p.Gly505Ser variant in POMGNT1 has been reported in four individuals with muscular dystrophy-dystroglycanopathy (PMID: 29302074, 33200426, 23689641, 32404165), and has been identified in 0.006% (1/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID:rs760705290). 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 been reported in ClinVar (Variation ID #553478) as pathogenic by Women's Health and Genetics/Laboratory Corporation of America, LabCorp, as likely pathogenic by 3Billion, and as a variant of uncertain significance (VUS) by Counsyl, Natera, Inc, and Invitae. Of the four affected individuals, one was a homozygote, which increases the likelihood that the p.Gly505Ser variant is pathogenic (PMID: 29302074). 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, the clinical significance of the p.Gly505Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_supporting, PP3 (Richards 2015). -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.074	T;T
Sift4G	Benign	0.093	T;T
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.91		Gain of catalytic residue at G505 (P = 0.0695);Gain of catalytic residue at G505 (P = 0.0695);
MVP		0.97
MPC		0.88
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.71
gMVP		0.92

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

Other links and lift over

dbSNP: rs760705290; hg19: chr1-46657796;