chr6-83181786-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_015599.3(PGM3):ā€‹c.737A>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

PGM3
NM_015599.3 missense

Scores

10
6
3

Clinical Significance

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

Conservation

PhyloP100: 7.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 140732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-83181786-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PGM3NM_015599.3 linkc.737A>G p.Asn246Ser missense_variant Exon 6 of 13 ENST00000513973.6 NP_056414.1 O95394-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PGM3ENST00000513973.6 linkc.737A>G p.Asn246Ser missense_variant Exon 6 of 13 1 NM_015599.3 ENSP00000424874.1 O95394-1
PGM3ENST00000283977.9 linkc.494A>G p.Asn165Ser missense_variant Exon 5 of 12 5 ENSP00000283977.5 J3KN95

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250886
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135592
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461472
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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
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
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
26
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
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Pathogenic
3.6
H;.;H;.;.;.
PrimateAI
Uncertain
0.50
T
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;.
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.87
MutPred
0.82
Gain of disorder (P = 0.0553);.;Gain of disorder (P = 0.0553);.;.;.;
MVP
0.95
MPC
0.68
ClinPred
0.99
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.78
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777562; hg19: chr6-83891505; API