rs201114442

Positions:

• chr3-43080978-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032806.6(POMGNT2):​c.454G>A​(p.Val152Met) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,614,216 control chromosomes in the GnomAD database, including 3 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 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (3 hom.)
• Consequence: POMGNT2 NM_032806.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023945928).
• BP6: Variant 3-43080978-C-T is Benign according to our data. Variant chr3-43080978-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00019 (29/152338) while in subpopulation EAS AF= 0.00193 (10/5172). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMGNT2	NM_032806.6	c.454G>A	p.Val152Met	missense_variant	2/2	ENST00000344697.3
POMGNT2	XM_005265515.4	c.454G>A	p.Val152Met	missense_variant	3/3
POMGNT2	XM_011534163.3	c.454G>A	p.Val152Met	missense_variant	3/3
POMGNT2	XM_017007353.2	c.454G>A	p.Val152Met	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT2	ENST00000344697.3	c.454G>A	p.Val152Met	missense_variant	2/2	1	NM_032806.6	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251410 Hom.: 2 AF XY: 0.000258 AC XY: 35 AN XY: 135880

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00190

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461878 Hom.: 3 Cov.: 37 AF XY: 0.000129 AC XY: 94 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00161

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74494

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the POMGNT2 protein (p.Val152Met). This variant is present in population databases (rs201114442, gnomAD 0.2%). 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: 473279). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. -

POMGNT2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

POMGNT2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.17	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.10	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.99	D;D
Vest4		0.56
MVP		0.78
MPC		0.75
ClinPred		0.073	T
GERP RS		5.0
Varity_R		0.070
gMVP		0.61

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: rs201114442; hg19: chr3-43122470;