NM_000289.6:c.2087G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000289.6(PFKM):c.2087G>A(p.Arg696His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,446 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.014 ( 174 hom. )

Consequence

PFKM
NM_000289.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009243131).

BP6

Variant 12-48145125-G-A is Benign according to our data. Variant chr12-48145125-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1597/152328) while in subpopulation NFE AF= 0.0179 (1216/68030). AF 95% confidence interval is 0.017. There are 11 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6 link	c.2087G>A	p.Arg696His	missense_variant	Exon 21 of 23	ENST00000359794.11	NP_000280.1	P08237-1A0A024R0Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11 link	c.2087G>A	p.Arg696His	missense_variant	Exon 21 of 23	1	NM_000289.6	ENSP00000352842.5		P08237-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1596

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00820

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00969

AC:

2436

AN:

251424

Hom.:

AF XY:

0.00960

AC XY:

1305

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00163

Gnomad SAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.00730

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0145

AC:

21175

AN:

1461118

Hom.:

174

Cov.:

AF XY:

0.0140

AC XY:

10211

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00624

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.000806

Gnomad4 SAS exome

AF:

0.00248

Gnomad4 FIN exome

AF:

0.00760

Gnomad4 NFE exome

AF:

0.0174

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.0105

AC:

1597

AN:

152328

Hom.:

Cov.:

AF XY:

0.00954

AC XY:

711

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00820

Gnomad4 NFE

AF:

0.0179

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0150

Hom.:

Bravo

AF:

0.00965

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.00969

AC:

1177

Asia WGS

AF:

0.00202

AC:

AN:

3478

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:5

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22133655, 7825568, 22995991, 20981092) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PFKM: PP2, BS1, BS2 -

Jan 09, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0092

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

MetaSVM

Uncertain

-0.053

MutationAssessor

Uncertain

2.5

M;M;.;.;.;M;M;.;M;M

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

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

REVEL

Pathogenic

0.65

Sift

Benign

0.061

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

Sift4G

Benign

0.099

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

Polyphen

0.98

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

Vest4

0.68, 0.68, 0.67, 0.77, 0.68

MVP

0.86

MPC

1.7

ClinPred

0.035

GERP RS

5.0

Varity_R

0.63

gMVP

0.82

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