12-48143841-A-G

Variant names:

• chr12-48143841-A-G
• rs4075913
• NM_000289.6:c.1880+27A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.1880+27A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,576,994 control chromosomes in the GnomAD database, including 511,957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46277 hom., cov: 32)
  • Exomes 𝑓: 0.80 (465680 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0700
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-48143841-A-G is Benign according to our data. Variant chr12-48143841-A-G is described in ClinVar as Benign. ClinVar VariationId is 255754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

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.1880+27A>G		intron	N/A	NP_000280.1
	PFKM	NM_001354735.1		c.2189+27A>G		intron	N/A	NP_001341664.1
	PFKM	NM_001354736.1		c.2189+27A>G		intron	N/A	NP_001341665.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.1880+27A>G		intron	N/A	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.1880+27A>G		intron	N/A	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.1880+27A>G		intron	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117609 AN: 152024 Hom.: 46245 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.722 AC: 181457 AN: 251394 AF XY: 0.731

Gnomad AFR exome AF: 0.777

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.759

GnomAD4 exome AF: 0.802 AC: 1142296 AN: 1424852 Hom.: 465680 Cov.: 25 AF XY: 0.799 AC XY: 568188 AN XY: 711166

African (AFR) AF: 0.774 AC: 25348 AN: 32764

American (AMR) AF: 0.499 AC: 22287 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 20596 AN: 25902

East Asian (EAS) AF: 0.417 AC: 16487 AN: 39492

South Asian (SAS) AF: 0.671 AC: 57346 AN: 85472

European-Finnish (FIN) AF: 0.764 AC: 40803 AN: 53410

Middle Eastern (MID) AF: 0.829 AC: 4718 AN: 5694

European-Non Finnish (NFE) AF: 0.843 AC: 908574 AN: 1078302

Other (OTH) AF: 0.780 AC: 46137 AN: 59140

GnomAD4 genome AF: 0.774 AC: 117689 AN: 152142 Hom.: 46277 Cov.: 32 AF XY: 0.764 AC XY: 56820 AN XY: 74364

African (AFR) AF: 0.777 AC: 32232 AN: 41480

American (AMR) AF: 0.638 AC: 9745 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3472

East Asian (EAS) AF: 0.410 AC: 2120 AN: 5172

South Asian (SAS) AF: 0.647 AC: 3122 AN: 4824

European-Finnish (FIN) AF: 0.766 AC: 8112 AN: 10594

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 57000 AN: 68004

Other (OTH) AF: 0.771 AC: 1630 AN: 2114

Alfa AF: 0.800 Hom.: 9332

Bravo AF: 0.762

Asia WGS AF: 0.546 AC: 1903 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glycogen storage disease, type VII (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4075913; hg19: chr12-48537624;