12-48107434-G-A

Position:

• chr12-48107434-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001354735.1(PFKM):​c.61G>A​(p.Val21Ile) 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. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_001354735.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PFKM. . Gene score misZ 2.3591 (greater than the threshold 3.09). Trascript score misZ 4.0504 (greater than threshold 3.09). GenCC has associacion of gene with glycogen storage disease VII.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20550537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_001354735.1	c.61G>A	p.Val21Ile	missense_variant	2/26
PFKM	NM_001354736.1	c.61G>A	p.Val21Ile	missense_variant	2/26
PFKM	NM_001166686.2	c.61G>A	p.Val21Ile	missense_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000642730.1	c.61G>A	p.Val21Ile	missense_variant	2/26
PFKM	ENST00000340802.12	c.61G>A	p.Val21Ile	missense_variant	2/25	2
PFKM	ENST00000549366.5	c.61G>A	p.Val21Ile	missense_variant	2/7	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2019

Variant is only present in a single alternate transcript of the PFKM gene (NM_001166686.1), but not in any other known transcript, including the primary isoform used by the Human Gene Mutation database (NM_000289.5); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0084	.;T;T;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T;T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.010	N;N;N;.;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Benign	0.36	T;T;D;.;D;D
Vest4		0.20
MutPred		0.31		Gain of catalytic residue at R18 (P = 0.0047);Gain of catalytic residue at R18 (P = 0.0047);Gain of catalytic residue at R18 (P = 0.0047);Gain of catalytic residue at R18 (P = 0.0047);Gain of catalytic residue at R18 (P = 0.0047);Gain of catalytic residue at R18 (P = 0.0047);
MVP		0.62
MPC		0.015
ClinPred		1.0	D
GERP RS		3.9
gMVP		0.085

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48501217;