rs41291971

Variant names:

• chr12-48145125-G-A
• rs41291971
• NM_000289.6:c.2087G>A
• PFKM p.Arg696His

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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:12
• Conservation: PhyloP100: 9.94
• Publications: 22 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000289.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.2087G>A	p.Arg696His	missense	Exon 21 of 23	NP_000280.1	P08237-1
	PFKM	NM_001354735.1		c.2396G>A	p.Arg799His	missense	Exon 24 of 26	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.2396G>A	p.Arg799His	missense	Exon 24 of 26	NP_001341665.1	A0A2R8Y891

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.2087G>A	p.Arg696His	missense	Exon 21 of 23	ENSP00000352842.5	P08237-1
	PFKM	ENST00000312352.11	TSL:1	c.2087G>A	p.Arg696His	missense	Exon 21 of 23	ENSP00000309438.7	P08237-1
	PFKM	ENST00000547587.5	TSL:1	c.2087G>A	p.Arg696His	missense	Exon 20 of 22	ENSP00000449426.1	P08237-1

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

GnomAD2 exomes AF: 0.00969 AC: 2436 AN: 251424 AF XY: 0.00960

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 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

African (AFR) AF: 0.00206 AC: 69 AN: 33474

American (AMR) AF: 0.00624 AC: 279 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 137 AN: 26128

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39698

South Asian (SAS) AF: 0.00248 AC: 214 AN: 86244

European-Finnish (FIN) AF: 0.00760 AC: 406 AN: 53416

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0174 AC: 19354 AN: 1111298

Other (OTH) AF: 0.0111 AC: 672 AN: 60368

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

African (AFR) AF: 0.00308 AC: 128 AN: 41576

American (AMR) AF: 0.00725 AC: 111 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00820 AC: 87 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1216 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0147 Hom.: 77

Bravo AF: 0.00965

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type VII (5)
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.65
Sift	Benign	0.061	T
Sift4G	Benign	0.099	T
Varity_R		0.63
gMVP		0.82
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41291971;

hg19: chr12-48538908;

COSMIC: COSV100402319;

COSMIC: COSV100402319;