6-83172034-A-G

Variant names:

• chr6-83172034-A-G
• rs1554257039
• NM_015599.3:c.1268T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015599.3(PGM3):​c.1268T>C​(p.Met423Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M423R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM3 NM_015599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.95
• Publications: 1 publications found

Genes affected

PGM3 (HGNC:8907): (phosphoglucomutase 3) This gene encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. A non-synonymous single nucleotide polymorphism in this gene may play a role in resistance to diabetic nephropathy and neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

PGM3 Gene-Disease associations (from GenCC):

• immunodeficiency 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 6-83172034-A-G is Pathogenic according to our data. Variant chr6-83172034-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475000.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM3	NM_015599.3	c.1268T>C	p.Met423Thr	missense_variant	Exon 11 of 13	ENST00000513973.6	NP_056414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM3	ENST00000513973.6	c.1268T>C	p.Met423Thr	missense_variant	Exon 11 of 13	1	NM_015599.3	ENSP00000424874.1
PGM3	ENST00000283977.9	c.1025T>C	p.Met342Thr	missense_variant	Exon 10 of 12	5		ENSP00000283977.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jan 11, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531373, 33534079) -

Immunodeficiency 23 Uncertain:1

Jul 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with threonine at codon 451 of the PGM3 protein (p.Met451Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PGM3-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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;T;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.97	D;.;.;.;.;.
Vest4		0.90
MutPred		0.70		Loss of stability (P = 0.014);.;Loss of stability (P = 0.014);.;.;.;
MVP		0.73
MPC		0.70
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.95
Mutation Taster		=5/95	disease causing

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: rs1554257039; hg19: chr6-83881753;