12-48118502-C-A

Position:

• chr12-48118502-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001354735.1(PFKM):​c.226C>A​(p.Gln76Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,505,510 control chromosomes in the GnomAD database, including 521,697 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57948 hom., cov: 31)
  • Exomes 𝑓: 0.83 (463749 hom.)
• Consequence: PFKM NM_001354735.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.437

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.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PFKM. . Gene score misZ 2.3591 (greater than the threshold 3.09). Trascript score misZ 4.0504 (greater than threshold 3.09). GenCC has associacion of gene with glycogen storage disease VII.
• BP4: Computational evidence support a benign effect (MetaRNN=6.907633E-7).
• BP6: Variant 12-48118502-C-A is Benign according to our data. Variant chr12-48118502-C-A is described in ClinVar as [Benign]. Clinvar id is 1327006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48118502-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_001354735.1	c.226C>A	p.Gln76Lys	missense_variant	4/26
PFKM	NM_001354736.1	c.226C>A	p.Gln76Lys	missense_variant	4/26
PFKM	XM_047428999.1	c.436C>A	p.Gln146Lys	missense_variant	4/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000642730.1	c.226C>A	p.Gln76Lys	missense_variant	4/26
PFKM	ENST00000549366.5	c.226C>A	p.Gln76Lys	missense_variant	4/7	4
PFKM	ENST00000546755.5	c.226C>A	p.Gln76Lys	missense_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132255 AN: 152076 Hom.: 57890 Cov.: 31

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.887

GnomAD3 exomes AF: 0.851 AC: 109039 AN: 128104 Hom.: 46605 AF XY: 0.849 AC XY: 59562 AN XY: 70146

Gnomad AFR exome AF: 0.971

Gnomad AMR exome AF: 0.848

Gnomad ASJ exome AF: 0.841

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.837

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.854

GnomAD4 exome AF: 0.826 AC: 1118124 AN: 1353316 Hom.: 463749 Cov.: 27 AF XY: 0.826 AC XY: 553409 AN XY: 669652

Gnomad4 AFR exome AF: 0.974

Gnomad4 AMR exome AF: 0.850

Gnomad4 ASJ exome AF: 0.835

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.837

Gnomad4 FIN exome AF: 0.841

Gnomad4 NFE exome AF: 0.812

Gnomad4 OTH exome AF: 0.848

GnomAD4 genome AF: 0.870 AC: 132369 AN: 152194 Hom.: 57948 Cov.: 31 AF XY: 0.872 AC XY: 64837 AN XY: 74394

Gnomad4 AFR AF: 0.967

Gnomad4 AMR AF: 0.859

Gnomad4 ASJ AF: 0.834

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.829

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.888

Alfa AF: 0.841 Hom.: 12569

Bravo AF: 0.877

TwinsUK AF: 0.815 AC: 3023

ALSPAC AF: 0.813 AC: 3133

ExAC AF: 0.804 AC: 11526

Asia WGS AF: 0.942 AC: 3275 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.011	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.26	T;T;T
MetaRNN	Benign	6.9e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-0.010	N;N;.
REVEL	Benign	0.098
Sift	Pathogenic	0.0	D;T;.
Sift4G	Uncertain	0.0040	.;D;.
ClinPred		0.012	T
GERP RS		0.89
gMVP		0.18

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4760682; hg19: chr12-48512285;