chr12-48118502-C-T

Variant names:

• chr12-48118502-C-T
• rs4760682
• NM_001354735.1:c.226C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001354735.1(PFKM):​c.226C>T​(p.Gln76*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,359,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PFKM NM_001354735.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.437
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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_001354735.1		c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26	NP_001341665.1	A0A2R8Y891
	PFKM	NM_001354741.2		c.-60C>T		5_prime_UTR	Exon 2 of 24	NP_001341670.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000642730.1		c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26	ENSP00000496597.1	A0A2R8Y891
	PFKM	ENST00000549366.5	TSL:4	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 7	ENSP00000449622.1	F8VVE3
	PFKM	ENST00000546755.5	TSL:4	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 5	ENSP00000450173.1	F8VNZ1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1359920 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 672634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31252

American (AMR) AF: 0.00 AC: 0 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 35612

South Asian (SAS) AF: 0.00 AC: 0 AN: 78798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.46e-7 AC: 1 AN: 1057412

Other (OTH) AF: 0.00 AC: 0 AN: 57044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.088	N
PhyloP100		0.44
GERP RS		0.89
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4760682; hg19: chr12-48512285;