12-48119244-C-A

Variant names:

• chr12-48119244-C-A
• rs41291959
• NM_001354740.1:c.-83C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001354740.1(PFKM):​c.-83C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 977,034 control chromosomes in the GnomAD database, including 4,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (356 hom., cov: 31)
  • Exomes 𝑓: 0.090 (3654 hom.)
• Consequence: PFKM NM_001354740.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-48119244-C-A is Benign according to our data. Variant chr12-48119244-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 308945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.-171C>A		upstream_gene_variant		ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.-171C>A		upstream_gene_variant		1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0599 AC: 9104 AN: 151998 Hom.: 356 Cov.: 31

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0898 AC: 74107 AN: 824918 Hom.: 3654 Cov.: 20 AF XY: 0.0901 AC XY: 34346 AN XY: 381228

African (AFR) AF: 0.0180 AC: 284 AN: 15744

American (AMR) AF: 0.0450 AC: 44 AN: 978

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 92 AN: 5134

East Asian (EAS) AF: 0.00248 AC: 9 AN: 3630

South Asian (SAS) AF: 0.0157 AC: 258 AN: 16408

European-Finnish (FIN) AF: 0.0616 AC: 18 AN: 292

Middle Eastern (MID) AF: 0.0179 AC: 29 AN: 1624

European-Non Finnish (NFE) AF: 0.0948 AC: 71461 AN: 754004

Other (OTH) AF: 0.0705 AC: 1912 AN: 27104

GnomAD4 genome AF: 0.0599 AC: 9106 AN: 152116 Hom.: 356 Cov.: 31 AF XY: 0.0581 AC XY: 4324 AN XY: 74364

African (AFR) AF: 0.0245 AC: 1015 AN: 41512

American (AMR) AF: 0.0408 AC: 623 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4816

European-Finnish (FIN) AF: 0.0839 AC: 887 AN: 10578

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0930 AC: 6320 AN: 67956

Other (OTH) AF: 0.0535 AC: 113 AN: 2114

Alfa AF: 0.0779 Hom.: 212

Bravo AF: 0.0534

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease, type VII Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		1.3
PromoterAI		0.040	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41291959; hg19: chr12-48513027;