rs587777562

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_015599.3(PGM3):c.737A>G(p.Asn246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PGM3
NM_015599.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.67

Publications

8 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: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 6-83181786-T-C is Pathogenic according to our data. Variant chr6-83181786-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 140732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM3	NM_015599.3 link	c.737A>G	p.Asn246Ser	missense_variant	Exon 6 of 13	ENST00000513973.6	NP_056414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM3	ENST00000513973.6 link	c.737A>G	p.Asn246Ser	missense_variant	Exon 6 of 13	1	NM_015599.3	ENSP00000424874.1
PGM3	ENST00000283977.9 link	c.494A>G	p.Asn165Ser	missense_variant	Exon 5 of 12	5		ENSP00000283977.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250886

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461472

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.0000224

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 23

Pathogenic:3

Jul 03, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jan 21, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Homozygous missense variation in exon 7 of the PGM3 gene that results in the amino acid substitution of Serine for Asparagine at codon 274 was detected. The observed variant c.821A>G (p.Asn274Ser) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, MutPred, PROVEAN and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

Jul 03, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

segregates with the phenotype in an affected family

Inborn genetic diseases

Pathogenic:1

May 11, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.821A>G (p.N274S) alteration is located in exon 7 (coding exon 6) of the PGM3 gene. This alteration results from an A to G substitution at nucleotide position 821, causing the asparagine (N) at amino acid position 274 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250886) total alleles studied. The highest observed frequency was 0.005% (1/18382) of East Asian alleles. This alteration, also known as c.737A>G (p.Asn246Ser), was reported in multiple homozygous individuals with clinical features of PGM3-related immunodeficiency (Stray-Pedersen, 2014; Bernth-Jensen, 2016; NCBI ClinVar 2022)._x000D_ _x000D_ ClinVar citation: National Center for Biotechnology Information. ClinVar; [VCV000140732.3], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000140732.3 (accessed May 11, 2023). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, N274S is deleterious. The variant disrupts the interaction of Asn274 with metal-binding loop and active serine loop (Stray-Pedersen, 2014; Raimi, 2018). In vitro expression studies in E. coli demonstrated that this substitution abolished PGM3 function with residual function of approximately 1% compared to wild type (Stray-Pedersen, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Severe combined immunodeficiency disease

Pathogenic:1

Jul 29, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PGM3 c.821A>G (p.Asn274Ser) results in a conservative amino acid change located in the Phosphoacetylglucosamine mutase AMG1, domain II (IPR049023) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250886 control chromosomes. c.821A>G (also known as c.737A>G , p.Asn246Ser) has been reported in the literature in individuals affected with PGM3-related immunodeficiency (examples: Stray-Pedersen_2014 and Bernth-Jensen_2016). 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 <10% of normal activity ( Stray-Pedersen_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24931394, 26409661). ClinVar contains an entry for this variant (Variation ID: 140732). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;T;.;.;.;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.6

H;.;H;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.0

D;.;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;.

Vest4

0.87

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.90

Mutation Taster

=1/99

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