rs41291963

chr12-48134194-G-A

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.594-38G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00775 in 1,593,824 control chromosomes in the GnomAD database, including 175 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 (99 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.888

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 12-48134194-G-A is Benign according to our data. Variant chr12-48134194-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255764.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 (2950/152282) while in subpopulation AFR AF= 0.0484 (2012/41546). AF 95% confidence interval is 0.0467. There are 76 homozygotes in gnomad4. There are 1498 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKM	NM_000289.6	c.594-38G>A		intron_variant		ENST00000359794.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKM	ENST00000359794.11	c.594-38G>A		intron_variant		1	NM_000289.6	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2915 AN: 152164 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0109 AC: 2739 AN: 251464 Hom.: 43 AF XY: 0.00982 AC XY: 1335 AN XY: 135912

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00652 AC: 9400 AN: 1441542 Hom.: 99 Cov.: 29 AF XY: 0.00641 AC XY: 4603 AN XY: 718554

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.00365

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0194 AC: 2950 AN: 152282 Hom.: 76 Cov.: 32 AF XY: 0.0201 AC XY: 1498 AN XY: 74458

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.0325

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0144 Hom.: 4

Bravo AF: 0.0196

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.5
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41291963; hg19: chr12-48527977;