dbSNP rs774790041: PFKM:p.Asp4Glu (chr12-48107385-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001354735.1(PFKM):c.12C>G(p.Asp4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D4D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PFKM
NM_001354735.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06156829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PFKM	NM_001354735.1 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 26	NP_001341664.1
PFKM	NM_001354736.1 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 26	NP_001341665.1
PFKM	NM_001166686.2 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 25	NP_001160158.1	P08237-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
PFKM	ENST00000642730.1 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 26		ENSP00000496597.1	A0A2R8Y891
PFKM	ENST00000340802.12 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 25	2	ENSP00000345771.6	P08237-3
PFKM	ENST00000549366.5 link	c.12C>G	p.Asp4Glu	missense_variant	Exon 2 of 7	4	ENSP00000449622.1	F8VVE3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719344

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109488

Other (OTH)

AF:

0.00

AC:

AN:

60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0060

.;T;T;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.43

T;T;T;T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.062

T;T;T;T;T;T

MetaSVM

Benign

-0.75

PhyloP100

-0.013

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.18

N;N;N;.;N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T;T;.;T;T

Sift4G

Benign

0.23

T;D;D;.;D;D

Vest4

0.049

MutPred

0.33

Gain of catalytic residue at F6 (P = 0.0026);Gain of catalytic residue at F6 (P = 0.0026);Gain of catalytic residue at F6 (P = 0.0026);Gain of catalytic residue at F6 (P = 0.0026);Gain of catalytic residue at F6 (P = 0.0026);Gain of catalytic residue at F6 (P = 0.0026);

MVP

0.46

MPC

0.016

ClinPred

0.64

GERP RS

-0.071

gMVP

0.054

Mutation Taster

=95/5

polymorphism

(source)

Splicing

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

Publications

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rs774790041

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over