rs2269933

Variant names:

• chr12-48133276-G-A
• rs2269933
• NM_000289.6:c.428-39G>A

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.428-39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,579,568 control chromosomes in the GnomAD database, including 71,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6657 hom., cov: 31)
  • Exomes 𝑓: 0.30 (64942 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.13
• Publications: 8 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 12-48133276-G-A is Benign according to our data. Variant chr12-48133276-G-A is described in ClinVar as Benign. ClinVar VariationId is 255762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.428-39G>A		intron_variant	Intron 5 of 22	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.428-39G>A		intron_variant	Intron 5 of 22	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44455 AN: 151856 Hom.: 6631 Cov.: 31

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.259 AC: 64859 AN: 250360 AF XY: 0.258

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.297 AC: 423500 AN: 1427594 Hom.: 64942 Cov.: 26 AF XY: 0.292 AC XY: 208087 AN XY: 712280

African (AFR) AF: 0.308 AC: 10124 AN: 32834

American (AMR) AF: 0.168 AC: 7504 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8316 AN: 25934

East Asian (EAS) AF: 0.233 AC: 9228 AN: 39554

South Asian (SAS) AF: 0.160 AC: 13720 AN: 85612

European-Finnish (FIN) AF: 0.247 AC: 13196 AN: 53390

Middle Eastern (MID) AF: 0.253 AC: 1437 AN: 5688

European-Non Finnish (NFE) AF: 0.317 AC: 342518 AN: 1080714

Other (OTH) AF: 0.295 AC: 17457 AN: 59194

GnomAD4 genome AF: 0.293 AC: 44520 AN: 151974 Hom.: 6657 Cov.: 31 AF XY: 0.287 AC XY: 21342 AN XY: 74286

African (AFR) AF: 0.308 AC: 12742 AN: 41420

American (AMR) AF: 0.253 AC: 3862 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1283 AN: 5172

South Asian (SAS) AF: 0.166 AC: 801 AN: 4824

European-Finnish (FIN) AF: 0.243 AC: 2566 AN: 10568

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21279 AN: 67928

Other (OTH) AF: 0.307 AC: 647 AN: 2110

Alfa AF: 0.297 Hom.: 3999

Bravo AF: 0.293

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type VII Benign:1

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.78
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2269933; hg19: chr12-48527059; COSMIC: COSV56656564; COSMIC: COSV56656564;