12-48145196-A-G

Position:

• chr12-48145196-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.2093-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,036 control chromosomes in the GnomAD database, including 34,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2441 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31623 hom.)
• Consequence: PFKM NM_000289.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.564

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-48145196-A-G is Benign according to our data. Variant chr12-48145196-A-G is described in ClinVar as [Benign]. Clinvar id is 255757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFKM	NM_000289.6	c.2093-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.2093-14A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000289.6	ENSP00000352842	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25283 AN: 152008 Hom.: 2439 Cov.: 32

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.178 AC: 44862 AN: 251360 Hom.: 4453 AF XY: 0.182 AC XY: 24761 AN XY: 135854

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.253

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.204 AC: 298028 AN: 1460910 Hom.: 31623 Cov.: 32 AF XY: 0.203 AC XY: 147277 AN XY: 726816

Gnomad4 AFR exome AF: 0.0689

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.166 AC: 25285 AN: 152126 Hom.: 2441 Cov.: 32 AF XY: 0.163 AC XY: 12124 AN XY: 74360

Gnomad4 AFR AF: 0.0725

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.203

Alfa AF: 0.207 Hom.: 4617

Bravo AF: 0.166

Asia WGS AF: 0.155 AC: 538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.10
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs11168427; hg19: chr12-48538979; COSMIC: COSV56656555; COSMIC: COSV56656555;