12-48107378-A-T

Position:

chr12-48107378-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -1.24

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=6.336159E-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
PFKM	NM_001354735.1 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	NM_001354736.1 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	NM_001166686.2 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	UniProt
PFKM	ENST00000642730.1 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/26
PFKM	ENST00000340802.12 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/25	2	P08237-3
PFKM	ENST00000549366.5 linkuse as main transcript	c.5A>T	p.His2Leu	missense_variant	2/7	4

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34536

AN:

152004

Hom.:

4665

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.200

AC XY:

143833

AN XY:

717684

show subpopulations

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.:

AF XY:

0.237

AC XY:

17606

AN XY:

74376

show subpopulations

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:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type VII

Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2Other:1

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. -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

5.3

DANN

Benign

0.85

DEOGEN2

Benign

0.0057

.;T;T;.;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.097

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

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

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

GERP RS

-2.3

gMVP

0.17

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over