12-48118502-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_001354735.1	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26		NP_001341664.1
PFKM	NM_001354736.1	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26		NP_001341665.1
PFKM	XM_047428999.1	c.436C>T	p.Gln146*	stop_gained	Exon 4 of 26		XP_047284955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000642730.1	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 26			ENSP00000496597.1
PFKM	ENST00000549366.5	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 7	4		ENSP00000449622.1
PFKM	ENST00000546755.5	c.226C>T	p.Gln76*	stop_gained	Exon 4 of 5	4		ENSP00000450173.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.46e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
GERP RS		0.89

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48512285;