rs1049392

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000359794.11(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 ENST00000359794.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.96
• Publications: 20 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359794.11. 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.516C>T	p.Thr172Thr	synonymous	Exon 6 of 23	NP_000280.1
	PFKM	NM_001354735.1		c.825C>T	p.Thr275Thr	synonymous	Exon 9 of 26	NP_001341664.1
	PFKM	NM_001354736.1		c.825C>T	p.Thr275Thr	synonymous	Exon 9 of 26	NP_001341665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.516C>T	p.Thr172Thr	synonymous	Exon 6 of 23	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.516C>T	p.Thr172Thr	synonymous	Exon 6 of 23	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.516C>T	p.Thr172Thr	synonymous	Exon 5 of 22	ENSP00000449426.1

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

GnomAD2 exomes AF: 0.142 AC: 35691 AN: 251214 AF XY: 0.141

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 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

African (AFR) AF: 0.324 AC: 10823 AN: 33456

American (AMR) AF: 0.0842 AC: 3766 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3184 AN: 26128

East Asian (EAS) AF: 0.177 AC: 7046 AN: 39700

South Asian (SAS) AF: 0.136 AC: 11708 AN: 86248

European-Finnish (FIN) AF: 0.161 AC: 8615 AN: 53416

Middle Eastern (MID) AF: 0.223 AC: 1283 AN: 5760

European-Non Finnish (NFE) AF: 0.135 AC: 149959 AN: 1111528

Other (OTH) AF: 0.149 AC: 8982 AN: 60380

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

African (AFR) AF: 0.320 AC: 13257 AN: 41442

American (AMR) AF: 0.111 AC: 1689 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3470

East Asian (EAS) AF: 0.151 AC: 776 AN: 5156

South Asian (SAS) AF: 0.133 AC: 640 AN: 4816

European-Finnish (FIN) AF: 0.151 AC: 1597 AN: 10570

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9243 AN: 67982

Other (OTH) AF: 0.161 AC: 339 AN: 2110

Alfa AF: 0.151 Hom.: 3272

Bravo AF: 0.192

Asia WGS AF: 0.144 AC: 503 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.139

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type VII (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.5
DANN	Benign	0.81
PhyloP100		-4.0
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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