6-83169251-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015599.3(PGM3):c.1612C>A(p.Pro538Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P538P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

PGM3
NM_015599.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.33

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 links:

DOP1A (HGNC:21194): (DOP1 leucine zipper like protein A) Predicted to be involved in Golgi to endosome transport and endoplasmic reticulum organization. Predicted to be located in Golgi membrane. Predicted to be active in endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

DOP1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39077285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM3	NM_015599.3 linkuse as main transcript	c.1612C>A	p.Pro538Thr	missense_variant	13/13	ENST00000513973.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM3	ENST00000513973.6 linkuse as main transcript	c.1612C>A	p.Pro538Thr	missense_variant	13/13	1	NM_015599.3	P1	O95394-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000474

AC:

119

AN:

251168

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000951

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000365

AC:

534

AN:

1461730

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

246

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.000618

Gnomad4 NFE exome

AF:

0.000431

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000177

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000561

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 23

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 05, 2022	This sequence change in PGM3 is predicted to replace proline with threonine at codon 538, p.(Pro538Thr). The proline residue is evolutionarily conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a small physicochemical difference between proline and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.09% (110/128,980 alleles, 1 homozygote) in the European (non-Finnish) population. This variant has been reported as a variant of uncertain significance (ClinVar ID: 252565), and to our knowledge has not been reported in the literature in any individuals with immunodeficiency. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 566 of the PGM3 protein (p.Pro566Thr). This variant is present in population databases (rs143654268, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. 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: 252565). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.20

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.4

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.9

D;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.047

D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.65

MVP

0.73

MPC

0.81

ClinPred

0.27

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over