6-83181786-T-C

Position:

• chr6-83181786-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.67

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]

ACMG classification

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/exons	MANE	UniProt
PGM3	NM_015599.3	c.737A>G	p.Asn246Ser	missense_variant	6/13	ENST00000513973.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM3	ENST00000513973.6	c.737A>G	p.Asn246Ser	missense_variant	6/13	1	NM_015599.3	P1

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

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

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

Submissions by phenotype

Immunodeficiency 23 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 21, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2014	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jul 03, 2014	segregates with the phenotype in an affected family -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 29, 2024

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;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
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

Other links and lift over

dbSNP: rs587777562; hg19: chr6-83891505;