rs56117548

Variant names:

• chr12-48141297-G-T
• rs56117548
• NM_000289.6:c.1342-14G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.1342-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,612,984 control chromosomes in the GnomAD database, including 803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (51 hom., cov: 32)
  • Exomes 𝑓: 0.029 (752 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.410
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-48141297-G-T is Benign according to our data. Variant chr12-48141297-G-T is described in ClinVar as Benign. ClinVar VariationId is 255750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.1342-14G>T		intron_variant	Intron 14 of 22	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.1342-14G>T		intron_variant	Intron 14 of 22	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3215 AN: 152156 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00791

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0253 AC: 6357 AN: 251428 AF XY: 0.0282

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00652

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0288 AC: 42094 AN: 1460710 Hom.: 752 Cov.: 31 AF XY: 0.0298 AC XY: 21691 AN XY: 726742

African (AFR) AF: 0.00490 AC: 164 AN: 33470

American (AMR) AF: 0.0105 AC: 470 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00976 AC: 255 AN: 26136

East Asian (EAS) AF: 0.00597 AC: 237 AN: 39696

South Asian (SAS) AF: 0.0559 AC: 4824 AN: 86220

European-Finnish (FIN) AF: 0.0274 AC: 1462 AN: 53420

Middle Eastern (MID) AF: 0.00834 AC: 48 AN: 5756

European-Non Finnish (NFE) AF: 0.0299 AC: 33185 AN: 1110924

Other (OTH) AF: 0.0240 AC: 1449 AN: 60366

GnomAD4 genome AF: 0.0211 AC: 3213 AN: 152274 Hom.: 51 Cov.: 32 AF XY: 0.0213 AC XY: 1588 AN XY: 74456

African (AFR) AF: 0.00570 AC: 237 AN: 41552

American (AMR) AF: 0.0148 AC: 227 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.00792 AC: 41 AN: 5174

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4820

European-Finnish (FIN) AF: 0.0256 AC: 272 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2021 AN: 68012

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0222 Hom.: 8

Bravo AF: 0.0185

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Mar 23, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.62
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs56117548; hg19: chr12-48535080; COSMIC: COSV107349446; COSMIC: COSV107349446;