12-48145699-T-G

Variant names:

• chr12-48145699-T-G
• rs8716
• NM_000289.6:c.2334T>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000289.6(PFKM):​c.2334T>G​(p.Ala778Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,540 control chromosomes in the GnomAD database, including 106,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7298 hom., cov: 32)
  • Exomes 𝑓: 0.36 (99245 hom.)
• Consequence: PFKM NM_000289.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-48145699-T-G is Benign according to our data. Variant chr12-48145699-T-G is described in ClinVar as [Benign]. Clinvar id is 255758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48145699-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.2334T>G	p.Ala778Ala	synonymous_variant	Exon 23 of 23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.2334T>G	p.Ala778Ala	synonymous_variant	Exon 23 of 23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43408 AN: 151998 Hom.: 7299 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.316 AC: 79487 AN: 251320 Hom.: 14400 AF XY: 0.328 AC XY: 44521 AN XY: 135846

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.374

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.360 AC: 526152 AN: 1461424 Hom.: 99245 Cov.: 38 AF XY: 0.361 AC XY: 262772 AN XY: 727052

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.373

Gnomad4 FIN exome AF: 0.354

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.285 AC: 43409 AN: 152116 Hom.: 7298 Cov.: 32 AF XY: 0.284 AC XY: 21092 AN XY: 74334

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.295

Alfa AF: 0.366 Hom.: 12457

Bravo AF: 0.268

Asia WGS AF: 0.208 AC: 726 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.379

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:6

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.49

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: rs8716; hg19: chr12-48539482; COSMIC: COSV56660739; COSMIC: COSV56660739;