12-48130393-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000289.6(PFKM):​c.116G>C​(p.Arg39Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.87
• Publications: 7 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-48130393-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1157.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 12-48130393-G-C is Pathogenic according to our data. Variant chr12-48130393-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.116G>C	p.Arg39Pro	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>C	p.Arg39Pro	missense_variant	Exon 3 of 23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727150

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111826

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Pathogenic:4

Jan 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 14, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 39 of the PFKM protein (p.Arg39Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 7513946, 9443500). ClinVar contains an entry for this variant (Variation ID: 1154). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PFKM protein function with a positive predictive value of 80%. This variant disrupts the p.Arg39 amino acid residue in PFKM. Other variant(s) that disrupt this residue have been observed in individuals with PFKM-related conditions (PMID: 8037209, 27066546), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.;D;D;D;.;D;.;D;D;D;.;.;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
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	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;.;H;.;.;.;.;.;.;.;H;H;.;.;H;.;H;H
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;D;.;.;D;.;D;D
Vest4		0.98, 0.98, 0.97, 0.99, 0.97
MutPred		0.94		Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);.;.;.;.;.;.;.;Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);
MVP		0.93
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		1.0
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs121918193; hg19: chr12-48524176;