3-43081361-C-T

Position:

chr3-43081361-C-T

Variant summary

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

The NM_032806.6(POMGNT2):c.71G>A(p.Arg24Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,608,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

POMGNT2
NM_032806.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.33

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=0.053028762).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000427 (65/152284) while in subpopulation AMR AF= 0.00111 (17/15308). AF 95% confidence interval is 0.000707. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.71G>A	p.Arg24Gln	missense_variant	2/2	ENST00000344697.3	NP_116195.2
POMGNT2	XM_005265515.4 linkuse as main transcript	c.71G>A	p.Arg24Gln	missense_variant	3/3		XP_005265572.1
POMGNT2	XM_011534163.3 linkuse as main transcript	c.71G>A	p.Arg24Gln	missense_variant	3/3		XP_011532465.1
POMGNT2	XM_017007353.2 linkuse as main transcript	c.71G>A	p.Arg24Gln	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.71G>A	p.Arg24Gln	missense_variant	2/2	1	NM_032806.6	ENSP00000344125	P1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000338

AC:

AN:

242922

Hom.:

AF XY:

0.000242

AC XY:

AN XY:

132366

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000434

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000437

AC:

637

AN:

1456612

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

295

AN XY:

724740

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000763

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.000488

Gnomad4 OTH exome

AF:

0.000763

GnomAD4 genome

AF:

0.000427

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000437

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2021	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2016

- -

POMGNT2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The POMGNT2 c.71G>A variant is predicted to result in the amino acid substitution p.Arg24Gln. This variant has been reported in the homozygous state in an acutely ill infant (eTable 2 in Maron et al 2023. PubMed ID: 37432431). This variant is reported in 0.071% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.71G>A (p.R24Q) alteration is located in exon 2 (coding exon 1) of the POMGNT2 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). 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 23, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the POMGNT2 protein (p.Arg24Gln). This variant is present in population databases (rs139245562, gnomAD 0.08%). 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: 436370). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

0.085

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.0048

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

.;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.80

D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

0.20

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.24

T;T

Polyphen

0.17

B;B

Vest4

0.19

MVP

0.64

MPC

0.30

ClinPred

0.029

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.080

gMVP

0.48

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