NM_001354735.1:c.-10+299G>A

Variant names:

• chr12-48106551-G-A
• rs726354
• NM_001354735.1:c.-10+299G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354735.1(PFKM):​c.-10+299G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 209,332 control chromosomes in the GnomAD database, including 6,405 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4671 hom., cov: 31)
  • Exomes 𝑓: 0.22 (1734 hom.)
• Consequence: PFKM NM_001354735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• 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 rank	MANE	Protein	UniProt
PFKM	NM_001354735.1	c.-10+299G>A		intron_variant	Intron 1 of 25		NP_001341664.1
PFKM	NM_001354736.1	c.-10+240G>A		intron_variant	Intron 1 of 25		NP_001341665.1
PFKM	NM_001166686.2	c.-10+414G>A		intron_variant	Intron 1 of 24		NP_001160158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000642730.1	c.-10+299G>A		intron_variant	Intron 1 of 25			ENSP00000496597.1
PFKM	ENST00000550257.7	c.91+414G>A		intron_variant	Intron 1 of 23	4		ENSP00000447997.3
PFKM	ENST00000340802.12	c.-10+414G>A		intron_variant	Intron 1 of 24	2		ENSP00000345771.6

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34493 AN: 151838 Hom.: 4660 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.244

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: 0.143

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.224 AC: 12873 AN: 57374 Hom.: 1734 Cov.: 0 AF XY: 0.236 AC XY: 7200 AN XY: 30534

African (AFR) AF: 0.197 AC: 137 AN: 694

American (AMR) AF: 0.427 AC: 1511 AN: 3540

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 301 AN: 1470

East Asian (EAS) AF: 0.586 AC: 714 AN: 1218

South Asian (SAS) AF: 0.320 AC: 3436 AN: 10732

European-Finnish (FIN) AF: 0.230 AC: 649 AN: 2824

Middle Eastern (MID) AF: 0.174 AC: 32 AN: 184

European-Non Finnish (NFE) AF: 0.162 AC: 5449 AN: 33654

Other (OTH) AF: 0.211 AC: 644 AN: 3058

GnomAD4 genome AF: 0.227 AC: 34532 AN: 151958 Hom.: 4671 Cov.: 31 AF XY: 0.237 AC XY: 17582 AN XY: 74276

African (AFR) AF: 0.223 AC: 9254 AN: 41424

American (AMR) AF: 0.364 AC: 5555 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3464

East Asian (EAS) AF: 0.590 AC: 3042 AN: 5156

South Asian (SAS) AF: 0.353 AC: 1695 AN: 4806

European-Finnish (FIN) AF: 0.234 AC: 2472 AN: 10570

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11071 AN: 67954

Other (OTH) AF: 0.229 AC: 482 AN: 2106

Alfa AF: 0.199 Hom.: 519

Bravo AF: 0.239

Asia WGS AF: 0.454 AC: 1574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.4
DANN	Benign	0.77
PhyloP100		0.25
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs726354; hg19: chr12-48500334;