rs41291967

Positions:

• chr12-48141859-C-T

Variant summary

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

The NM_000289.6(PFKM):​c.1500+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,612,842 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (100 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.311

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-48141859-C-T is Benign according to our data. Variant chr12-48141859-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255751.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 = 0.0194 (2949/152242) while in subpopulation AFR AF= 0.0483 (2007/41540). AF 95% confidence interval is 0.0466. There are 76 homozygotes in gnomad4. There are 1502 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFKM	NM_000289.6	c.1500+32C>T		intron_variant		ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.1500+32C>T		intron_variant		1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2914 AN: 152124 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0109 AC: 2740 AN: 251302 Hom.: 43 AF XY: 0.00982 AC XY: 1334 AN XY: 135828

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.00539

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00649 AC: 9475 AN: 1460600 Hom.: 100 Cov.: 31 AF XY: 0.00637 AC XY: 4626 AN XY: 726710

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0194 AC: 2949 AN: 152242 Hom.: 76 Cov.: 32 AF XY: 0.0202 AC XY: 1502 AN XY: 74450

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0325

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.00451

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0144 Hom.: 4

Bravo AF: 0.0195

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glycogen storage disease, type VII Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.60

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: rs41291967; hg19: chr12-48535642;