rs200535361

Variant names:

• chr3-43080422-T-C
• rs200535361
• NM_032806.6:c.1010A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.17

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 -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 rank	MANE	Protein	UniProt
POMGNT2	NM_032806.6	c.1010A>G	p.Asn337Ser	missense_variant	Exon 2 of 2	ENST00000344697.3	NP_116195.2
POMGNT2	XM_005265515.4	c.1010A>G	p.Asn337Ser	missense_variant	Exon 3 of 3		XP_005265572.1
POMGNT2	XM_011534163.3	c.1010A>G	p.Asn337Ser	missense_variant	Exon 3 of 3		XP_011532465.1
POMGNT2	XM_017007353.2	c.1010A>G	p.Asn337Ser	missense_variant	Exon 4 of 4		XP_016862842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMGNT2	ENST00000344697.3	c.1010A>G	p.Asn337Ser	missense_variant	Exon 2 of 2	1	NM_032806.6	ENSP00000344125.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152164 Hom.: 0 Cov.: 33

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: 37 AN: 251298 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135848

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.: 1 Cov.: 37 AF XY: 0.000133 AC XY: 97 AN XY: 727234

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: 23 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74466

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.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Oct 16, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 18, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.53	T
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	T
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

Other links and lift over

dbSNP: rs200535361; hg19: chr3-43121914;