rs56117548

Positions:

• chr12-48141297-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.1342-14G>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.410

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
PFKM	NM_000289.6	c.1342-14G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.1342-14G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000289.6	ENSP00000352842	P1

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

GnomAD3 exomes AF: 0.0253 AC: 6357 AN: 251428 Hom.: 134 AF XY: 0.0282 AC XY: 3836 AN XY: 135880

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 SAS exome AF: 0.0571

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

Gnomad4 AFR exome AF: 0.00490

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00976

Gnomad4 EAS exome AF: 0.00597

Gnomad4 SAS exome AF: 0.0559

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0240

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

Gnomad4 AFR AF: 0.00570

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00792

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0279

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2016	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs56117548; hg19: chr12-48535080;