chr12-48132929-G-C

Variant names:

• chr12-48132929-G-C
• rs2228500
• NM_000289.6:c.299G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.594
• Publications: 44 publications found

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]

MIR6505 (HGNC:50104): (microRNA 6505) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000289.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.299G>C	p.Arg100Pro	missense	Exon 5 of 23	NP_000280.1
	PFKM	NM_001354735.1		c.608G>C	p.Arg203Pro	missense	Exon 8 of 26	NP_001341664.1
	PFKM	NM_001354736.1		c.608G>C	p.Arg203Pro	missense	Exon 8 of 26	NP_001341665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.299G>C	p.Arg100Pro	missense	Exon 5 of 23	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.299G>C	p.Arg100Pro	missense	Exon 5 of 23	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.299G>C	p.Arg100Pro	missense	Exon 4 of 22	ENSP00000449426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.59
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		0.21	B
Vest4		0.60
MutPred		0.66		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
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs2228500; hg19: chr12-48526712;