12-48107374-A-G

Variant names:

• chr12-48107374-A-G
• rs755094329
• NM_001354735.1:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001354735.1(PFKM):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,593,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PFKM NM_001354735.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 12 codons. Genomic position: 48107407. Lost 0.013 part of the original CDS.
• 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.1A>G	p.Met1?	start_lost	Exon 2 of 26		NP_001341664.1
PFKM	NM_001354736.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 26		NP_001341665.1
PFKM	NM_001166686.2	c.1A>G	p.Met1?	start_lost	Exon 2 of 25		NP_001160158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000642730.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 26			ENSP00000496597.1
PFKM	ENST00000340802.12	c.1A>G	p.Met1?	start_lost	Exon 2 of 25	2		ENSP00000345771.6
PFKM	ENST00000549366.5	c.1A>G	p.Met1?	start_lost	Exon 2 of 7	4		ENSP00000449622.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000854 AC: 2 AN: 234212 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1441072 Hom.: 0 Cov.: 27 AF XY: 0.00000279 AC XY: 2 AN XY: 717788

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33344

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39626

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86126

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 39124

Gnomad4 NFE exome AF: 0.00000362 AC: 4 AN: 1106256

Gnomad4 Remaining exome AF: 0.0000167 AC: 1 AN: 60060

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146981 AN: 0.0000146981

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000843 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type VII Uncertain:1

Mar 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0053	.;T;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
PROVEAN	Benign	0.030	N;N;N;.;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Uncertain	0.047	D;D;D;.;D;D
Vest4		0.55
MutPred		0.97		Gain of catalytic residue at F6 (P = 2e-04);Gain of catalytic residue at F6 (P = 2e-04);Gain of catalytic residue at F6 (P = 2e-04);Gain of catalytic residue at F6 (P = 2e-04);Gain of catalytic residue at F6 (P = 2e-04);Gain of catalytic residue at F6 (P = 2e-04);
MVP		0.73
ClinPred		0.99	D
GERP RS		2.8
gMVP		0.22
Mutation Taster		=79/121	disease causing

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755094329; hg19: chr12-48501157;