chr3-43080213-G-A

Variant names:

• chr3-43080213-G-A
• rs138480528
• NM_032806.6:c.1219C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_032806.6(POMGNT2):​c.1219C>T​(p.Arg407Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R407Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: POMGNT2 NM_032806.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.66
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myopathy caused by variation in POMGNT2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041891992).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000558 (85/152288) while in subpopulation AFR AF = 0.00166 (69/41550). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032806.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT2	NM_032806.6	MANE Select	c.1219C>T	p.Arg407Trp	missense	Exon 2 of 2	NP_116195.2
	POMGNT2	NM_001437285.1		c.1219C>T	p.Arg407Trp	missense	Exon 3 of 3	NP_001424214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMGNT2	ENST00000344697.3	TSL:1 MANE Select	c.1219C>T	p.Arg407Trp	missense	Exon 2 of 2	ENSP00000344125.2
	POMGNT2	ENST00000441964.1	TSL:4	c.1219C>T	p.Arg407Trp	missense	Exon 3 of 3	ENSP00000408992.1
	POMGNT2	ENST00000686643.1		c.1219C>T	p.Arg407Trp	missense	Exon 4 of 4	ENSP00000509123.1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 250824 AF XY: 0.000147

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000317 AC: 463 AN: 1461796 Hom.: 1 Cov.: 37 AF XY: 0.000278 AC XY: 202 AN XY: 727188

African (AFR) AF: 0.00191 AC: 64 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1111996

Other (OTH) AF: 0.000364 AC: 22 AN: 60390

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74468

African (AFR) AF: 0.00166 AC: 69 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.042	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.83
MPC		0.94
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.89
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs138480528; hg19: chr3-43121705; COSMIC: COSV100768064;