rs745508510

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_015599.3(PGM3):c.965T>C(p.Ile322Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,587,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PGM3
NM_015599.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 8.42

Publications

3 publications found

Variant links:

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

PGM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-83178737-A-G is Pathogenic according to our data. Variant chr6-83178737-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421723.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM3	NM_015599.3 link	c.965T>C	p.Ile322Thr	missense_variant	Exon 8 of 13	ENST00000513973.6	NP_056414.1	O95394-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM3	ENST00000513973.6 link	c.965T>C	p.Ile322Thr	missense_variant	Exon 8 of 13	1	NM_015599.3	ENSP00000424874.1		O95394-1
PGM3	ENST00000283977.9 link	c.722T>C	p.Ile241Thr	missense_variant	Exon 7 of 12	5		ENSP00000283977.5		J3KN95

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251152

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000418

AC:

AN:

1434962

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32936

American (AMR)

AF:

0.0000671

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39474

South Asian (SAS)

AF:

0.00

AC:

AN:

85680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1087690

Other (OTH)

AF:

0.0000168

AC:

AN:

59486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency 23

Pathogenic:2Uncertain:2

Dec 22, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PGM3 NM_001199917.1 exon 9 p.Ile350Thr (c.1049T>C): This variant has been reported in the literature (as p.Ile322Thr) as homozygous in 1 individual with recurrent infection, neutropenia and eosinophilia, segregating with disease in 1 affected family member (Bjorksten 1976 PMID:1245758, Lundin 2015 PMID:26482871). Of note, both unaffected parents and an unaffected sibling were identified to be heterozygous; two other siblings were also affected but did not receive genetic testing. This variant is present in 2/111592 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs745508510). This variant is present in ClinVar (Variation ID:421723). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant destabilizes the protein (Lundin 2015 PMID:26482871). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Apr 20, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 350 of the PGM3 protein (p.Ile350Thr). This variant is present in population databases (rs745508510, gnomAD 0.003%). This missense change has been observed in individual(s) with primary immunodeficiency without hyper-IgE levels (PMID: 26482871). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile322Thr. ClinVar contains an entry for this variant (Variation ID: 421723). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). Experimental studies have shown that this missense change affects PGM3 function (PMID: 26482871). 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. -

Jul 30, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Severe combined immunodeficiency disease

Pathogenic:1

Aug 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PGM3 c.1049T>C (p.Ile350Thr) results in a non-conservative amino acid change located in the Phosphoacetylglucosamine mutase AMG1, domain III (IPR049022) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251152 control chromosomes. c.1049T>C has been reported in the literature in homozygous and compound heterozygous individuals affected with Severe Combined Immunodeficiency (Lundin_2015, Winslow_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 480% of normal enzyme activity in an in vitro assay (Lundin_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26482871, 35040011). ClinVar contains an entry for this variant (Variation ID: 421723). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Jun 24, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on enzyme activity (PMID: 26482871); 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: 1245758, 35040011, 26482871, 28543917) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;T;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

2.9

M;.;M;.;.

PhyloP100

8.4

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.2

D;.;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;.;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.18

B;.;.;.;.

Vest4

0.69

MutPred

0.58

Loss of stability (P = 0.0047);.;Loss of stability (P = 0.0047);.;.;

MVP

0.83

MPC

0.36

ClinPred

0.90

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.72

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over