rs56009798

Variant names:

• chr12-48134191-A-G
• rs56009798
• NM_000289.6:c.594-41A>G

Variant summary

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

The ENST00000359794.11(PFKM):​c.594-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,586,814 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (90 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (56 hom.)
• Consequence: PFKM ENST00000359794.11 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.333
• Publications: 1 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=-0.87).
• BP6: Variant 12-48134191-A-G is Benign according to our data. Variant chr12-48134191-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359794.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.594-41A>G		intron	N/A	NP_000280.1
	PFKM	NM_001354735.1		c.903-41A>G		intron	N/A	NP_001341664.1
	PFKM	NM_001354736.1		c.903-41A>G		intron	N/A	NP_001341665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.594-41A>G		intron	N/A	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.594-41A>G		intron	N/A	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.594-41A>G		intron	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2598 AN: 152122 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00460 AC: 1157 AN: 251466 AF XY: 0.00336

Gnomad AFR exome AF: 0.0607

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00178 AC: 2557 AN: 1434574 Hom.: 56 Cov.: 29 AF XY: 0.00156 AC XY: 1114 AN XY: 715450

African (AFR) AF: 0.0611 AC: 2013 AN: 32922

American (AMR) AF: 0.00434 AC: 194 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5726

European-Non Finnish (NFE) AF: 0.0000598 AC: 65 AN: 1087136

Other (OTH) AF: 0.00441 AC: 262 AN: 59410

GnomAD4 genome AF: 0.0171 AC: 2605 AN: 152240 Hom.: 90 Cov.: 32 AF XY: 0.0165 AC XY: 1225 AN XY: 74460

African (AFR) AF: 0.0589 AC: 2444 AN: 41506

American (AMR) AF: 0.00765 AC: 117 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0112 Hom.: 18

Bravo AF: 0.0194

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56009798; hg19: chr12-48527974;