rs121918196

chr12-48145096-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000289.6(PFKM):c.2058G>T(p.Trp686Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.94

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PFKM
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 12-48145096-G-T is Pathogenic according to our data. Variant chr12-48145096-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1159.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_000289.6	c.2058G>T	p.Trp686Cys	missense_variant	21/23	ENST00000359794.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000359794.11	c.2058G>T	p.Trp686Cys	missense_variant	21/23	1	NM_000289.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Glycogen storage disease, type VII Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;.;.;.;D;D;.;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;M;M;.;M;M
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
Polyphen		1.0	D;D;.;.;.;D;D;D;D;D
Vest4		0.94, 0.95, 0.99, 0.94, 0.95
MutPred		0.89		Gain of catalytic residue at M684 (P = 3e-04);Gain of catalytic residue at M684 (P = 3e-04);.;.;.;Gain of catalytic residue at M684 (P = 3e-04);Gain of catalytic residue at M684 (P = 3e-04);.;Gain of catalytic residue at M684 (P = 3e-04);Gain of catalytic residue at M684 (P = 3e-04);
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs121918196; hg19: chr12-48538879; COSMIC: COSV100402553; COSMIC: COSV100402553;