rs41291971

chr12-48145125-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000289.6(PFKM):c.2087G>A(p.Arg696His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,446 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R696C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (174 hom.)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 9.94

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=0.009243131).
• BP6: Variant 12-48145125-G-A is Benign according to our data. Variant chr12-48145125-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1597/152328) while in subpopulation NFE AF= 0.0179 (1216/68030). AF 95% confidence interval is 0.017. There are 11 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_000289.6	c.2087G>A	p.Arg696His	missense_variant	21/23	ENST00000359794.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000359794.11	c.2087G>A	p.Arg696His	missense_variant	21/23	1	NM_000289.6	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1596 AN: 152210 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00969 AC: 2436 AN: 251424 Hom.: 20 AF XY: 0.00960 AC XY: 1305 AN XY: 135874

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00163

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00730

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0145 AC: 21175 AN: 1461118 Hom.: 174 Cov.: 31 AF XY: 0.0140 AC XY: 10211 AN XY: 726922

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.00760

Gnomad4 NFE exome AF: 0.0174

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0105 AC: 1597 AN: 152328 Hom.: 11 Cov.: 32 AF XY: 0.00954 AC XY: 711 AN XY: 74494

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0150 Hom.: 34

Bravo AF: 0.00965

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.00969 AC: 1177

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PFKM: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	This variant is associated with the following publications: (PMID: 22133655, 7825568, 22995991, 20981092) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;.;.;.;T;T;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0092	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
Polyphen		0.98	D;D;.;.;.;D;D;D;D;D
Vest4		0.68, 0.68, 0.67, 0.77, 0.68
MVP		0.86
MPC		1.7
ClinPred		0.035	T
GERP RS		5.0
Varity_R		0.63
gMVP		0.82

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: rs41291971; hg19: chr12-48538908; COSMIC: COSV100402319; COSMIC: COSV100402319;