rs149600978

Variant names:

• chr12-48134853-T-G
• rs149600978
• NM_000289.6:c.747+24T>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_000289.6(PFKM):​c.747+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,601,772 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.713
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-48134853-T-G is Benign according to our data. Variant chr12-48134853-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 255766.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 = 0.00832 (1267/152226) while in subpopulation AFR AF = 0.0277 (1150/41522). AF 95% confidence interval is 0.0264. There are 15 homozygotes in GnomAd4. There are 595 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_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.747+24T>G		intron	N/A	NP_000280.1	P08237-1
	PFKM	NM_001354735.1		c.1056+24T>G		intron	N/A	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.1056+24T>G		intron	N/A	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.747+24T>G		intron	N/A	ENSP00000352842.5	P08237-1
	PFKM	ENST00000312352.11	TSL:1	c.747+24T>G		intron	N/A	ENSP00000309438.7	P08237-1
	PFKM	ENST00000547587.5	TSL:1	c.747+24T>G		intron	N/A	ENSP00000449426.1	P08237-1

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152108 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00253 AC: 635 AN: 251456 AF XY: 0.00189

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00115 AC: 1660 AN: 1449546 Hom.: 17 Cov.: 27 AF XY: 0.000979 AC XY: 707 AN XY: 722018

African (AFR) AF: 0.0304 AC: 1010 AN: 33216

American (AMR) AF: 0.00208 AC: 93 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00641 AC: 254 AN: 39642

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 85956

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5744

European-Non Finnish (NFE) AF: 0.000126 AC: 139 AN: 1100862

Other (OTH) AF: 0.00247 AC: 148 AN: 59956

GnomAD4 genome AF: 0.00832 AC: 1267 AN: 152226 Hom.: 15 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74436

African (AFR) AF: 0.0277 AC: 1150 AN: 41522

American (AMR) AF: 0.00392 AC: 60 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5164

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00481 Hom.: 3

Bravo AF: 0.00974

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.7
DANN	Benign	0.62
PhyloP100		0.71
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: rs149600978; hg19: chr12-48528636;