rs201593125

Positions:

• chr6-83171948-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015599.3(PGM3):​c.1354C>A​(p.Leu452Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000761 in 1,612,912 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (4 hom.)
• Consequence: PGM3 NM_015599.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 5.34

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048125803).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM3	NM_015599.3	c.1354C>A	p.Leu452Ile	missense_variant	11/13	ENST00000513973.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM3	ENST00000513973.6	c.1354C>A	p.Leu452Ile	missense_variant	11/13	1	NM_015599.3	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000618 AC: 155 AN: 250656 Hom.: 0 AF XY: 0.000613 AC XY: 83 AN XY: 135406

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000558

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000775 AC: 1132 AN: 1460616 Hom.: 4 Cov.: 29 AF XY: 0.000758 AC XY: 551 AN XY: 726610

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000616

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.000884

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74480

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.000601

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000502 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 23 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2022	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 480 of the PGM3 protein (p.Leu480Ile). This variant is present in population databases (rs201593125, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PGM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 445475). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 27, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 08-15-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2020

The c.1438C>A (p.L480I) alteration is located in exon 12 (coding exon 11) of the PGM3 gene. This alteration results from a C to A substitution at nucleotide position 1438, causing the leucine (L) at amino acid position 480 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD) database, the PGM3 c.1438C>A alteration was observed in 0.06% (171/282058) of total alleles studied, with a frequency of 0.08% (30/35304) in the Latino subpopulation. This amino acid position is highly conserved in available vertebrate species. The p.L480I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;T;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;.;N;N;N;N
REVEL	Benign	0.091
Sift	Uncertain	0.028	D;.;T;D;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.21
MVP		0.46
MPC		0.38
ClinPred		0.053	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.47

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: rs201593125; hg19: chr6-83881667;