rs121918193

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The ENST00000359794.11(PFKM):​c.116G>A​(p.Arg39Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,872 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PFKM
ENST00000359794.11 missense

Scores

15
3
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.87
Variant links:
Genes affected
PFKM (HGNC:8877): (phosphofructokinase, muscle) Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-48130393-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PFKM. . Gene score misZ 2.3591 (greater than the threshold 3.09). Trascript score misZ 4.067 (greater than threshold 3.09). GenCC has associacion of gene with glycogen storage disease VII.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
PP5
Variant 12-48130393-G-A is Pathogenic according to our data. Variant chr12-48130393-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2137355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PFKMNM_000289.6 linkuse as main transcriptc.116G>A p.Arg39Gln missense_variant 3/23 ENST00000359794.11 NP_000280.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PFKMENST00000359794.11 linkuse as main transcriptc.116G>A p.Arg39Gln missense_variant 3/231 NM_000289.6 ENSP00000352842 P1P08237-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251484
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135920
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:
0.0000924
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461684
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type VII Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 39 of the PFKM protein (p.Arg39Gln). This variant is present in population databases (rs121918193, gnomAD 0.02%). This missense change has been observed in individual(s) with glycogen storage disease type VII (PMID: 27066546). ClinVar contains an entry for this variant (Variation ID: 2137355). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PFKM protein function with a positive predictive value of 80%. This variant disrupts the p.Arg39 amino acid residue in PFKM. Other variant(s) that disrupt this residue have been observed in individuals with PFKM-related conditions (PMID: 7513946, 8037209), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 09, 2023PP1, PP3, PP4, PM2_moderate, PM5 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D;.;D;.;D;D;D;.;D;.;D;D;D;.;.;D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
.;D;.;D;.;.;D;D;D;D;.;.;D;D;D;D;.;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Pathogenic
3.8
H;.;H;.;.;.;.;.;.;.;H;H;.;.;H;.;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;.;.;.;.;.;.;D;D;.;.;D;.;D;D
Vest4
0.94, 0.94, 0.92, 0.96, 0.90
MVP
0.88
MPC
1.2
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.97
gMVP
0.95

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: rs121918193; hg19: chr12-48524176; API