rs2228500

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000289.6(PFKM):c.299G>A(p.Arg100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,792 control chromosomes in the GnomAD database, including 34,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2442 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31611 hom. )

Consequence

PFKM
NM_000289.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.594

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]

PFKM links:

PFKM (HGNC:):

PFKM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017756522).

BP6

Variant 12-48132929-G-A is Benign according to our data. Variant chr12-48132929-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48132929-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFKM	NM_000289.6 linkuse as main transcript	c.299G>A	p.Arg100Gln	missense_variant	5/23	ENST00000359794.11	NP_000280.1	P08237-1A0A024R0Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11 linkuse as main transcript	c.299G>A	p.Arg100Gln	missense_variant	5/23	1	NM_000289.6	ENSP00000352842.5		P08237-1

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25223

AN:

151988

Hom.:

2440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0724

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.282

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.149

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.204

GnomAD3 exomes

AF:

0.178

AC:

44734

AN:

251114

Hom.:

4418

AF XY:

0.182

AC XY:

24696

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.0689

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.252

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.204

AC:

298112

AN:

1461686

Hom.:

31611

Cov.:

AF XY:

0.203

AC XY:

147325

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0690

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.269

Gnomad4 EAS exome

AF:

0.227

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.135

Gnomad4 NFE exome

AF:

0.217

Gnomad4 OTH exome

AF:

0.203

GnomAD4 genome

AF:

0.166

AC:

25225

AN:

152106

Hom.:

2442

Cov.:

AF XY:

0.163

AC XY:

12085

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0724

Gnomad4 AMR

AF:

0.177

Gnomad4 ASJ

AF:

0.282

Gnomad4 EAS

AF:

0.242

Gnomad4 SAS

AF:

0.148

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.215

Gnomad4 OTH

AF:

0.202

Alfa

AF:

0.208

Hom.:

8713

Bravo

AF:

0.166

TwinsUK

AF:

0.218

AC:

810

ALSPAC

AF:

0.209

AC:

804

ESP6500AA

AF:

0.0710

AC:

313

ESP6500EA

AF:

0.224

AC:

1923

ExAC

AF:

0.177

AC:

21515

Asia WGS

AF:

0.155

AC:

538

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.234

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VII

Benign:6

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Glycogen storage disease VII, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 =>Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;T;.;T;.;T;T;.;.;T;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.89

.;D;.;D;.;D;.;.;D;D;D;.;D

MetaRNN

Benign

0.0018

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.47

N;.;N;.;.;.;N;N;.;N;.;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N;.;N;N;.;N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.24

T;T;.;T;T;.;T;T;T;T;T;T;T

Sift4G

Benign

0.17

T;T;.;T;T;.;T;T;T;T;T;T;T

Polyphen

0.0030

B;.;B;.;.;.;B;B;.;B;.;B;B

Vest4

0.062, 0.068, 0.050, 0.079

MPC

0.67

ClinPred

0.0082

GERP RS

1.7

Varity_R

0.13

gMVP

0.58

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.

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