rs116172105

Variant names:

• chr12-48131272-A-G
• rs116172105
• NM_000289.6:c.160-44A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001354735.1(PFKM):​c.469-44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,342,366 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (13 hom.)
• Consequence: PFKM NM_001354735.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.459
• Publications: 0 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=-0.84).
• BP6: Variant 12-48131272-A-G is Benign according to our data. Variant chr12-48131272-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 255752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00718 (1093/152322) while in subpopulation AFR AF = 0.0251 (1043/41566). AF 95% confidence interval is 0.0238. There are 15 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354735.1. 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.160-44A>G		intron	N/A	NP_000280.1
	PFKM	NM_001354735.1		c.469-44A>G		intron	N/A	NP_001341664.1
	PFKM	NM_001354736.1		c.469-44A>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.160-44A>G		intron	N/A	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.160-44A>G		intron	N/A	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.160-44A>G		intron	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152204 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00204 AC: 513 AN: 250998 AF XY: 0.00171

Gnomad AFR exome AF: 0.0291

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000793 AC: 944 AN: 1190044 Hom.: 13 Cov.: 17 AF XY: 0.000674 AC XY: 408 AN XY: 604978

African (AFR) AF: 0.0279 AC: 787 AN: 28242

American (AMR) AF: 0.00117 AC: 52 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24460

East Asian (EAS) AF: 0.00 AC: 0 AN: 38438

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.000574 AC: 3 AN: 5230

European-Non Finnish (NFE) AF: 0.0000324 AC: 28 AN: 863940

Other (OTH) AF: 0.00140 AC: 72 AN: 51260

GnomAD4 genome AF: 0.00718 AC: 1093 AN: 152322 Hom.: 15 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74486

African (AFR) AF: 0.0251 AC: 1043 AN: 41566

American (AMR) AF: 0.00177 AC: 27 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68034

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00351 Hom.: 3

Bravo AF: 0.00873

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.6
DANN	Benign	0.72
PhyloP100		0.46
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs116172105; hg19: chr12-48525055;