rs147129872

chr3-43080318-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_032806.6(POMGNT2):c.1114G>A(p.Asp372Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: POMGNT2 NM_032806.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24350116).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000138 (21/152126) while in subpopulation AFR AF= 0.000386 (16/41422). AF 95% confidence interval is 0.000242. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. 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	UniProt
POMGNT2	NM_032806.6	c.1114G>A	p.Asp372Asn	missense_variant	2/2	ENST00000344697.3
POMGNT2	XM_005265515.4	c.1114G>A	p.Asp372Asn	missense_variant	3/3
POMGNT2	XM_011534163.3	c.1114G>A	p.Asp372Asn	missense_variant	3/3
POMGNT2	XM_017007353.2	c.1114G>A	p.Asp372Asn	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMGNT2	ENST00000344697.3	c.1114G>A	p.Asp372Asn	missense_variant	2/2	1	NM_032806.6	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251446 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135900

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461862 Hom.: 0 Cov.: 37 AF XY: 0.0000220 AC XY: 16 AN XY: 727230

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74304

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Invitae

Nov 19, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 372 of the POMGNT2 protein (p.Asp372Asn). This variant is present in population databases (rs147129872, 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: 578252). 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) performed at Invitae indicates that this missense variant is not expected to disrupt POMGNT2 protein function with a negative predictive value of 80%. 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	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.14	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.38	B;B
Vest4		0.26
MVP		0.81
MPC		0.80
ClinPred		0.078	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.40

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: rs147129872; hg19: chr3-43121810;