rs1049392

Variant names:

• chr12-48133403-C-T
• rs1049392
• NM_000289.6:c.516C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000289.6(PFKM):​c.516C>T​(p.Thr172Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,364 control chromosomes in the GnomAD database, including 18,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3227 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15698 hom.)
• Consequence: PFKM NM_000289.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.96

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-48133403-C-T is Benign according to our data. Variant chr12-48133403-C-T is described in ClinVar as [Benign]. Clinvar id is 255763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.516C>T	p.Thr172Thr	synonymous_variant	Exon 6 of 23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.516C>T	p.Thr172Thr	synonymous_variant	Exon 6 of 23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28186 AN: 151908 Hom.: 3228 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.142 AC: 35691 AN: 251214 Hom.: 2968 AF XY: 0.141 AC XY: 19144 AN XY: 135758

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.141 AC: 205366 AN: 1461338 Hom.: 15698 Cov.: 33 AF XY: 0.141 AC XY: 102527 AN XY: 726978

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.0842

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.185 AC: 28196 AN: 152026 Hom.: 3227 Cov.: 32 AF XY: 0.184 AC XY: 13654 AN XY: 74312

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.161

Alfa AF: 0.147 Hom.: 2493

Bravo AF: 0.192

Asia WGS AF: 0.144 AC: 503 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:5

Jan 13, 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. -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 21, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.5
DANN	Benign	0.81

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: rs1049392; hg19: chr12-48527186; COSMIC: COSV56658232; COSMIC: COSV56658232;