12-48107378-A-T

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.5A>T(p.His2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,593,076 control chromosomes in the GnomAD database, including 40,698 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4676 hom., cov: 32)
  • Exomes 𝑓: 0.20 (36022 hom.)
• Consequence: PFKM NM_001354735.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -1.24

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 where missense usually causes diseases, PFKM
• BP4: Computational evidence support a benign effect (MetaRNN=6.336159E-5).
• BP6: Variant 12-48107378-A-T is Benign according to our data. Variant chr12-48107378-A-T is described in ClinVar as [Benign]. Clinvar id is 441153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48107378-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_001354735.1	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	NM_001354736.1	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	NM_001166686.2	c.5A>T	p.His2Leu	missense_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000642730.1	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	ENST00000340802.12	c.5A>T	p.His2Leu	missense_variant	2/25	2
PFKM	ENST00000549366.5	c.5A>T	p.His2Leu	missense_variant	2/7	4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34536 AN: 152004 Hom.: 4665 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.282 AC: 65970 AN: 234192 Hom.: 12355 AF XY: 0.271 AC XY: 34712 AN XY: 128232

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.585

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.198 AC: 284596 AN: 1440954 Hom.: 36022 Cov.: 29 AF XY: 0.200 AC XY: 143833 AN XY: 717684

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.583

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.227 AC: 34574 AN: 152122 Hom.: 4676 Cov.: 32 AF XY: 0.237 AC XY: 17606 AN XY: 74376

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.229

Alfa AF: 0.193 Hom.: 2099

Bravo AF: 0.239

TwinsUK AF: 0.160 AC: 594

ALSPAC AF: 0.163 AC: 629

ESP6500AA AF: 0.228 AC: 714

ESP6500EA AF: 0.170 AC: 1217

ExAC AF: 0.266 AC: 31472

Asia WGS AF: 0.454 AC: 1574 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	5.3
Dann	Benign	0.85
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.42	T;T;T;T;T;T
MetaRNN	Benign	0.000063	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.17	N;N;N;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.056	T;T;T;.;T;T
Sift4G	Pathogenic	0.0	D;D;D;.;D;D
Vest4		0.13
MPC		0.038
ClinPred		0.019	T
GERP RS		-2.3
gMVP		0.17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11609399; hg19: chr12-48501161; COSMIC: COSV50286825; COSMIC: COSV50286825;