chr3-43080573-C-T

Position:

• chr3-43080573-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032806.6(POMGNT2):​c.859G>A​(p.Glu287Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POMGNT2 NM_032806.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37743133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT2	NM_032806.6	c.859G>A	p.Glu287Lys	missense_variant	2/2	ENST00000344697.3	NP_116195.2
POMGNT2	XM_005265515.4	c.859G>A	p.Glu287Lys	missense_variant	3/3		XP_005265572.1
POMGNT2	XM_011534163.3	c.859G>A	p.Glu287Lys	missense_variant	3/3		XP_011532465.1
POMGNT2	XM_017007353.2	c.859G>A	p.Glu287Lys	missense_variant	4/4		XP_016862842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMGNT2	ENST00000344697.3	c.859G>A	p.Glu287Lys	missense_variant	2/2	1	NM_032806.6	ENSP00000344125.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2018

This sequence change replaces glutamic acid with lysine at codon 287 of the POMGNT2 protein (p.Glu287Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POMGNT2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	0.030
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.41	N;N
REVEL	Benign	0.19
Sift	Benign	0.15	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.085	B;B
Vest4		0.55
MutPred		0.56		Gain of ubiquitination at E287 (P = 0.0311);Gain of ubiquitination at E287 (P = 0.0311);
MVP		0.69
MPC		0.42
ClinPred		0.45	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.60

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: rs774815839; hg19: chr3-43122065;