rs11552507

Positions:

• chr12-48132936-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000289.6(PFKM):​c.306C>T​(p.Ala102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,614,122 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (32 hom., cov: 32)
  • Exomes 𝑓: 0.023 (459 hom.)
• Consequence: PFKM NM_000289.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.338

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-48132936-C-T is Benign according to our data. Variant chr12-48132936-C-T is described in ClinVar as [Benign]. Clinvar id is 255761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48132936-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0189 (2871/152270) while in subpopulation NFE AF= 0.0289 (1963/68014). AF 95% confidence interval is 0.0278. There are 32 homozygotes in gnomad4. There are 1402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFKM	NM_000289.6	c.306C>T	p.Ala102Ala	synonymous_variant	5/23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.306C>T	p.Ala102Ala	synonymous_variant	5/23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2872 AN: 152152 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.0452

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0196 AC: 4916 AN: 251300 Hom.: 65 AF XY: 0.0192 AC XY: 2605 AN XY: 135800

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00451

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0227 AC: 33178 AN: 1461852 Hom.: 459 Cov.: 34 AF XY: 0.0224 AC XY: 16265 AN XY: 727228

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0189 AC: 2871 AN: 152270 Hom.: 32 Cov.: 32 AF XY: 0.0188 AC XY: 1402 AN XY: 74448

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0316

Gnomad4 NFE AF: 0.0289

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0261 Hom.: 31

Bravo AF: 0.0165

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0257

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:5

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -

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 24, 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

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs11552507; hg19: chr12-48526719;