12-48107378-A-C

Variant names:

• chr12-48107378-A-C
• rs11609399
• NM_001354735.1:c.5A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354735.1(PFKM):​c.5A>C​(p.His2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. 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. H2L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_001354735.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 25 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]

PFKM Gene-Disease associations (from GenCC):

• glycogen storage disease VII

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1918143).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354735.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_001354735.1		c.5A>C	p.His2Pro	missense	Exon 2 of 26	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.5A>C	p.His2Pro	missense	Exon 2 of 26	NP_001341665.1	A0A2R8Y891
	PFKM	NM_001166686.2		c.5A>C	p.His2Pro	missense	Exon 2 of 25	NP_001160158.1	P08237-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000642730.1		c.5A>C	p.His2Pro	missense	Exon 2 of 26	ENSP00000496597.1	A0A2R8Y891
	PFKM	ENST00000340802.12	TSL:2	c.5A>C	p.His2Pro	missense	Exon 2 of 25	ENSP00000345771.6	P08237-3
	PFKM	ENST00000549366.5	TSL:4	c.5A>C	p.His2Pro	missense	Exon 2 of 7	ENSP00000449622.1	F8VVE3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.5
DANN	Benign	0.84
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.50	T
PhyloP100		-1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.19
Sift	Benign	0.048	D
Sift4G	Pathogenic	0.0	D
Vest4		0.36
MutPred		0.29		Gain of catalytic residue at H2 (P = 5e-04)
MVP		0.52
MPC		0.039
ClinPred		0.25	T
GERP RS		-2.3
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs11609399; hg19: chr12-48501161;