NM_000289.6:c.1880+32G>C

Variant names:

• chr12-48143846-G-C
• rs4075914
• NM_000289.6:c.1880+32G>C

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+32G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,541,192 control chromosomes in the GnomAD database, including 5,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (355 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5452 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.967
• Publications: 5 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=-0.83).
• BP6: Variant 12-48143846-G-C is Benign according to our data. Variant chr12-48143846-G-C is described in ClinVar as Benign. ClinVar VariationId is 255755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0909 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+32G>C		intron	N/A	NP_000280.1
	PFKM	NM_001354735.1		c.2189+32G>C		intron	N/A	NP_001341664.1
	PFKM	NM_001354736.1		c.2189+32G>C		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+32G>C		intron	N/A	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.1880+32G>C		intron	N/A	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.1880+32G>C		intron	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes AF: 0.0594 AC: 9037 AN: 152170 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0929

Gnomad OTH AF: 0.0540

GnomAD2 exomes AF: 0.0572 AC: 14370 AN: 251380 AF XY: 0.0573

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0829

Gnomad NFE exome AF: 0.0906

Gnomad OTH exome AF: 0.0575

GnomAD4 exome AF: 0.0816 AC: 113334 AN: 1388904 Hom.: 5452 Cov.: 23 AF XY: 0.0793 AC XY: 55152 AN XY: 695328

African (AFR) AF: 0.0204 AC: 655 AN: 32064

American (AMR) AF: 0.0284 AC: 1269 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 437 AN: 25684

East Asian (EAS) AF: 0.000483 AC: 19 AN: 39376

South Asian (SAS) AF: 0.0162 AC: 1378 AN: 84856

European-Finnish (FIN) AF: 0.0837 AC: 4467 AN: 53394

Middle Eastern (MID) AF: 0.0153 AC: 86 AN: 5632

European-Non Finnish (NFE) AF: 0.0966 AC: 101024 AN: 1045332

Other (OTH) AF: 0.0690 AC: 3999 AN: 57918

GnomAD4 genome AF: 0.0594 AC: 9039 AN: 152288 Hom.: 355 Cov.: 32 AF XY: 0.0575 AC XY: 4284 AN XY: 74468

African (AFR) AF: 0.0243 AC: 1010 AN: 41564

American (AMR) AF: 0.0369 AC: 565 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4830

European-Finnish (FIN) AF: 0.0839 AC: 890 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6313 AN: 68010

Other (OTH) AF: 0.0534 AC: 113 AN: 2116

Alfa AF: 0.0716 Hom.: 84

Bravo AF: 0.0528

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.8
DANN	Benign	0.67
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4075914; hg19: chr12-48537629;