chr12-48132929-G-C

Position:

• chr12-48132929-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000289.6(PFKM):​c.299G>C​(p.Arg100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.594

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFKM	NM_000289.6	c.299G>C	p.Arg100Pro	missense_variant	5/23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.299G>C	p.Arg100Pro	missense_variant	5/23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;D;.;D;.;D;D;.;.;D;D;D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.95	.;D;.;D;.;D;.;.;D;D;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.;.;M;M;.;M;.;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D;.;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D;D;.;D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;.;D;D;.;D;D;D;D;D;D;D
Polyphen		0.21	B;.;B;.;.;.;B;B;.;B;.;B;B
Vest4		0.60, 0.60, 0.60, 0.62, 0.60
MutPred		0.66		Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);.;.;.;Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);Loss of MoRF binding (P = 5e-04);
MVP		0.63
MPC		0.86
ClinPred		0.86	D
GERP RS		1.7
Varity_R		0.93
gMVP		0.96

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

Other links and lift over

dbSNP: rs2228500; hg19: chr12-48526712;