rs1555206566

Variant names:

• chr12-48140868-GC-AA
• rs1555206566
• NM_000289.6:c.1338_1339delGCinsAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000289.6(PFKM):​c.1338_1339delGCinsAA​(p.Gln447Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G446G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKM NM_000289.6 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.57
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-48140868-GC-AA is Benign according to our data. Variant chr12-48140868-GC-AA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526619.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000289.6. 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.1338_1339delGCinsAA	p.Gln447Lys	missense splice_region	N/A	NP_000280.1
	PFKM	NM_001354735.1		c.1647_1648delGCinsAA	p.Gln550Lys	missense splice_region	N/A	NP_001341664.1
	PFKM	NM_001354736.1		c.1647_1648delGCinsAA	p.Gln550Lys	missense splice_region	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.1338_1339delGCinsAA	p.Gln447Lys	missense splice_region	N/A	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.1338_1339delGCinsAA	p.Gln447Lys	missense splice_region	N/A	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.1338_1339delGCinsAA	p.Gln447Lys	missense splice_region	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Glycogen storage disease, type VII (2)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555206566; hg19: chr12-48534651;