12-48130393-G-T

Variant names:

• chr12-48130393-G-T
• rs121918193
• NM_000289.6:c.116G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000289.6(PFKM):​c.116G>T​(p.Arg39Leu) 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: 9.87

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 12-48130393-G-T is Pathogenic according to our data. Variant chr12-48130393-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1157.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.116G>T	p.Arg39Leu	missense_variant	Exon 3 of 23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Aug 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D;.;D;D;D;.;D;.;D;D;D;.;.;D;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;D;.;.;D;D;D;D;.;.;D;D;D;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	M;.;M;.;.;.;.;.;.;.;M;M;.;.;M;.;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;.;D;.;.;.;.;.;.;.;D;D;.;.;P;.;D;D
Vest4		0.95, 0.95, 0.95, 0.93
MutPred		0.96		Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);Loss of MoRF binding (P = 0.003);
MVP		0.91
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121918193; hg19: chr12-48524176;