12-48118502-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001354735.1(PFKM):c.226C>A(p.Gln76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,505,510 control chromosomes in the GnomAD database, including 521,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57948 hom., cov: 31)

Exomes 𝑓: 0.83 ( 463749 hom. )

Consequence

PFKM
NM_001354735.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.437

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease VII
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics

PFKM links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.907633E-7).

BP6

Variant 12-48118502-C-A is Benign according to our data. Variant chr12-48118502-C-A is described in ClinVar as [Benign]. Clinvar id is 1327006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
PFKM	NM_001354735.1 link	c.226C>A	p.Gln76Lys	missense_variant	Exon 4 of 26	NP_001341664.1
PFKM	NM_001354736.1 link	c.226C>A	p.Gln76Lys	missense_variant	Exon 4 of 26	NP_001341665.1
PFKM	XM_047428999.1 link	c.436C>A	p.Gln146Lys	missense_variant	Exon 4 of 26	XP_047284955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
PFKM	ENST00000642730.1 link	c.226C>A	p.Gln76Lys	missense_variant	Exon 4 of 26		ENSP00000496597.1	A0A2R8Y891
PFKM	ENST00000549366.5 link	c.226C>A	p.Gln76Lys	missense_variant	Exon 4 of 7	4	ENSP00000449622.1	F8VVE3
PFKM	ENST00000546755.5 link	c.226C>A	p.Gln76Lys	missense_variant	Exon 4 of 5	4	ENSP00000450173.1	F8VNZ1

Frequencies

GnomAD3 genomes

AF:

0.870

AC:

132255

AN:

152076

Hom.:

57890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.967

Gnomad AMI

AF:

0.783

Gnomad AMR

AF:

0.859

Gnomad ASJ

AF:

0.834

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.859

Gnomad FIN

AF:

0.829

Gnomad MID

AF:

0.848

Gnomad NFE

AF:

0.812

Gnomad OTH

AF:

0.887

GnomAD2 exomes

AF:

0.851

AC:

109039

AN:

128104

AF XY:

0.849

show subpopulations

Gnomad AFR exome

AF:

0.971

Gnomad AMR exome

AF:

0.848

Gnomad ASJ exome

AF:

0.841

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.841

Gnomad NFE exome

AF:

0.814

Gnomad OTH exome

AF:

0.854

GnomAD4 exome

AF:

0.826

AC:

1118124

AN:

1353316

Hom.:

463749

Cov.:

AF XY:

0.826

AC XY:

553409

AN XY:

669652

show subpopulations

African (AFR)

AF:

0.974

AC:

30414

AN:

31236

American (AMR)

AF:

0.850

AC:

30297

AN:

35656

Ashkenazi Jewish (ASJ)

AF:

0.835

AC:

20853

AN:

24968

East Asian (EAS)

AF:

0.999

AC:

35590

AN:

35610

South Asian (SAS)

AF:

0.837

AC:

65878

AN:

78674

European-Finnish (FIN)

AF:

0.841

AC:

28130

AN:

33456

Middle Eastern (MID)

AF:

0.861

AC:

4864

AN:

5648

European-Non Finnish (NFE)

AF:

0.812

AC:

853870

AN:

1051202

Other (OTH)

AF:

0.848

AC:

48228

AN:

56866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

7947

15895

23842

31790

39737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.870

AC:

132369

AN:

152194

Hom.:

57948

Cov.:

AF XY:

0.872

AC XY:

64837

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.967

AC:

40189

AN:

41554

American (AMR)

AF:

0.859

AC:

13123

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.834

AC:

2895

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5173

AN:

5178

South Asian (SAS)

AF:

0.858

AC:

4137

AN:

4820

European-Finnish (FIN)

AF:

0.829

AC:

8780

AN:

10588

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.812

AC:

55231

AN:

67984

Other (OTH)

AF:

0.888

AC:

1875

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

850

1700

2550

3400

4250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.866

Hom.:

28354

Bravo

AF:

0.877

TwinsUK

AF:

0.815

AC:

3023

ALSPAC

AF:

0.813

AC:

3133

ExAC

AF:

0.804

AC:

11526

Asia WGS

AF:

0.942

AC:

3275

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VII

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.011

T;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.26

T;T;T

MetaRNN

Benign

6.9e-7

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.44

PROVEAN

Benign

-0.010

N;N;.

REVEL

Benign

0.098

Sift

Pathogenic

0.0

D;T;.

Sift4G

Uncertain

0.0040

.;D;.

ClinPred

0.012

GERP RS

0.89

gMVP

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-48118502-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over