12-48108249-A-C

Position:

• chr12-48108249-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001354735.1(PFKM):​c.205+55A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,537,112 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: PFKM NM_001354735.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.39

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=-0.8).
• BP6: Variant 12-48108249-A-C is Benign according to our data. Variant chr12-48108249-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1201026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00963 (1466/152302) while in subpopulation AFR AF= 0.0338 (1405/41548). AF 95% confidence interval is 0.0323. There are 28 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_001166686.2	c.205+55A>C		intron_variant
PFKM	NM_001354735.1	c.205+55A>C		intron_variant
PFKM	NM_001354736.1	c.205+55A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000340802.12	c.205+55A>C		intron_variant		2
PFKM	ENST00000546755.5	c.205+55A>C		intron_variant		4
PFKM	ENST00000548288.5	c.205+55A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1462 AN: 152184 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00102 AC: 1416 AN: 1384810 Hom.: 18 AF XY: 0.000872 AC XY: 601 AN XY: 689072

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000247

Gnomad4 FIN exome AF: 0.0000263

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00963 AC: 1466 AN: 152302 Hom.: 28 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74480

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00497 Hom.: 4

Bravo AF: 0.0114

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	- -
Likely 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	-0.80
CADD	Benign	14
DANN	Benign	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111629833; hg19: chr12-48502032;