chr3-43080422-T-C

Position:

chr3-43080422-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_032806.6(POMGNT2):c.1010A>G(p.Asn337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

POMGNT2
NM_032806.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

POMGNT2 (HGNC:25902): (protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4-)) This gene encodes a protein with glycosyltransferase activity although its function is not currently known. [provided by RefSeq, Sep 2012]

POMGNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05992663).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000129 (188/1461866) while in subpopulation MID AF= 0.00676 (39/5768). AF 95% confidence interval is 0.00508. There are 1 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POMGNT2	NM_032806.6 linkuse as main transcript	c.1010A>G	p.Asn337Ser	missense_variant	2/2	ENST00000344697.3	NP_116195.2
POMGNT2	XM_005265515.4 linkuse as main transcript	c.1010A>G	p.Asn337Ser	missense_variant	3/3		XP_005265572.1
POMGNT2	XM_011534163.3 linkuse as main transcript	c.1010A>G	p.Asn337Ser	missense_variant	3/3		XP_011532465.1
POMGNT2	XM_017007353.2 linkuse as main transcript	c.1010A>G	p.Asn337Ser	missense_variant	4/4		XP_016862842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMGNT2	ENST00000344697.3 linkuse as main transcript	c.1010A>G	p.Asn337Ser	missense_variant	2/2	1	NM_032806.6	ENSP00000344125	P1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251298

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000151

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 18, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The c.1010A>G (p.N337S) alteration is located in exon 2 (coding exon 1) of the POMGNT2 gene. This alteration results from a A to G substitution at nucleotide position 1010, causing the asparagine (N) at amino acid position 337 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 337 of the POMGNT2 protein (p.Asn337Ser). This variant is present in population databases (rs200535361, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with POMGNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 436367). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.72

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.060

Sift

Benign

0.74

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0

B;B

Vest4

0.16

MVP

0.61

MPC

0.21

ClinPred

0.010

GERP RS

1.9

Varity_R

0.029

gMVP

0.37

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