12-48107378-A-G

Variant names:

• chr12-48107378-A-G
• rs11609399
• NM_001354735.1:c.5A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354735.1(PFKM):​c.5A>G​(p.His2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PFKM NM_001354735.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105489224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_001354735.1	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 26		NP_001341664.1
PFKM	NM_001354736.1	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 26		NP_001341665.1
PFKM	NM_001166686.2	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 25		NP_001160158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000642730.1	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 26			ENSP00000496597.1
PFKM	ENST00000340802.12	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 25	2		ENSP00000345771.6
PFKM	ENST00000549366.5	c.5A>G	p.His2Arg	missense_variant	Exon 2 of 7	4		ENSP00000449622.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443426 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 718774

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.4
DANN	Benign	0.60
DEOGEN2	Benign	0.0056	.;T;T;.;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.47	T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.080	N;N;N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.89	T;T;T;.;T;T
Sift4G	Pathogenic	0.0	D;D;D;.;D;D
Vest4		0.20
MutPred		0.27		Gain of catalytic residue at F6 (P = 0.002);Gain of catalytic residue at F6 (P = 0.002);Gain of catalytic residue at F6 (P = 0.002);Gain of catalytic residue at F6 (P = 0.002);Gain of catalytic residue at F6 (P = 0.002);Gain of catalytic residue at F6 (P = 0.002);
MVP		0.67
MPC		0.037
ClinPred		0.20	T
GERP RS		-2.3
gMVP		0.14

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11609399; hg19: chr12-48501161;